Inhibitors of hepatitis c virus

ABSTRACT

Compounds of Formula I are disclosed 
     
       
         
         
             
             
         
       
     
     As well as pharmaceutically acceptable salts thereof. Methods of using said compounds and pharmaceutical compositions containing said compounds are also disclosed.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.13/934,090, filed Jul. 2, 2013, which claims the benefit of U.S.Provisional Application No. 61/798,524, filed on Mar. 15, 2013, and U.S.Application No. 61/667,806, filed Jul. 3, 2012; which are hereinincorporated by reference in their entirety.

FIELD

Novel small molecule inhibitors of viral replication are disclosed,compositions containing such compounds, and therapeutic methodscomprising the administration of such compounds are also disclosed.

BACKGROUND

The hepatitis C virus (HCV), a member of the hepacivirus genera withinthe Flaviviridae family, is the leading cause of chronic liver diseaseworldwide (Boyer, N. et al. J Hepatol. 2000, 32, 98-112). Consequently,a significant focus of current antiviral research is directed toward thedevelopment of improved methods for the treatment of chronic HCVinfections in humans (Ciesek, S., von Hahn T., and Manns, M P., Clin.Liver Dis., 2011, 15, 597-609; Soriano, V. et al, J. Antimicrob.Chemother., 2011, 66, 1573-1686; Brody, H., Nature Outlook, 2011, 474,S1-S7; Gordon, C. P., et al., J. Med. Chem. 2005, 48, 1-20; Maradpour,D., et al., Nat. Rev. Micro. 2007, 5, 453-463).

Virologic cures of patients with chronic HCV infection are difficult toachieve because of the prodigious amount of daily virus production inchronically infected patients and the high spontaneous mutability of HCV(Neumann, et al., Science 1998, 282, 103-7; Fukimoto, et al.,Hepatology, 1996, 24, 1351-4; Domingo, et al., Gene 1985, 40, 1-8;Martell, et al., J. Virol. 1992, 66, 3225-9). HCV treatment is furthercomplicated by the fact that HCV is genetically diverse and expressed asseveral different genotypes and numerous subtypes. For example, HCV iscurrently classified into six major genotypes (designated 1-6), manysubtypes (designated a, b, c, and so on), and about 100 differentstrains (numbered 1, 2, 3, and so on).

HCV is distributed worldwide with genotypes 1, 2, and 3 predominatewithin the United States, Europe, Australia, and East Asia (Japan,Taiwan, Thailand, and China). Genotype 4 is largely found in the MiddleEast, Egypt and central Africa while genotype 5 and 6 are foundpredominantly in South Africa and South East Asia respectively(Simmonds, P. et al. J Virol. 84: 4597-4610, 2010).

The combination of ribavirin, a nucleoside analog, and interferon-alpha(a) (IFN), is utilized for the treatment of multiple genotypes ofchronic HCV infections in humans. However, the variable clinicalresponse observed within patients and the toxicity of this regimen havelimited its usefulness. Addition of a HCV protease inhibitor (telapreviror boceprevir) to the ribavirin and IFN regimen improves 12-weekpost-treatment virological response (SVR12) rates substantially.However, the regimen is currently only approved for genotype 1 patientsand toxicity and other side effects remain.

The use of directing acting antivirals to treat multiple genotypes ofHCV infection has proven challenging due to the variable activity ofantivirals against the different gentoypes. HCV protease inhibitorsfrequently have compromised in vitro activity against HCV genotypes 2and 3 compared to genotype 1 (See, e.g., Table 1 of Summa, V. et al.,Antimicrobial Agents and Chemotherapy, 2012, 56, 4161-4167; Gottwein, J.et al, Gastroenterology, 2011, 141, 1067-1079). Correspondingly,clinical efficacy has also proven highly variable across HCV genotypes.For example, therapies that are highly effective against HCV genotype 1and 2 may have limited or no clinical efficacy against genotype 3.(Moreno, C. et al., Poster 895, 61^(st) AASLD Meeting, Boston, Mass.,USA, Oct. 29-Nov. 2, 2010; Graham, F., et al, Gastroenterology, 2011,141, 881-889; Foster, G. R. et al., EASL 45^(th) Annual Meeting, Apr.14-18, 2010, Vienna, Austria.) In some cases, antiviral agents have goodclinical efficacy against genotype 1, but lower and more variableagainst genotypes 2 and 3. (Reiser, M. et al., Hepatology, 2005, 41,832-835.) To overcome the reduced efficacy in genotype 3 patients,substantially higher doses of antiviral agents may be required toachieve substantial viral load reductions (Fraser, I P et al., Abstract#48, HEP DART 2011, Koloa, Hi., December 2011.)

Antiviral agents that are less susceptible to viral resistance are alsoneeded. For example, resistance mutations at positions 155 and 168 inthe HCV protease frequently cause a substantial decrease in antiviralefficacy of HCV protease inhibitors (Mani, N. Ann Forum Collab HIV Res.,2012, 14, 1-8; Romano, K P et al, PNAS, 2010, 107, 20986-20991; Lenz O,Antimicrobial agents and chemotherapy, 2010, 54, 1878-1887.)

In view of the limitations of current HCV therapy, there is a need todevelop more effective anti-HCV therapies. It would also be useful toprovide therapies that are effective against multiple HCV genotypes andsubtypes.

SUMMARY

Novel compounds that inhibit the hepatitis C virus (HCV) NS3 proteaseare disclosed. In certain embodiments, the compounds disclosed inhibitmultiple genotypes of the hepatitis C virus. These compounds are usefulfor the treatment of HCV infection and the related symptoms.

In one embodiment, a compound of Formula (IV):

or a stereoisomer, or a mixture of stereoisomers, or a pharmaceuticallyacceptable salt thereof, is provided, wherein:

-   -   J is C₁-C₄ alkyl or C₃-C₆ carbocyclyl, wherein C₁-C₄ alkyl or        C₃-C₆ carbocyclyl is optionally substituted with halogen, —OH,        aryl or cyano;    -   {circle around (T)} is C₃-C₅ carbocyclylene that is attached to        L and to the remainder of the compound through two adjacent        carbons, wherein said C₃-C₆ carbocyclylene is optionally        substituted with C₁-C₄ alkyl, C₁-C₃ haloalkyl, halogen, —OH, or        cyano, or {circle around (T)} is C₅-C₈ bicyclic carbocyclylene        that is attached to L and to the remainder of the compound        through two adjacent carbons;    -   L is C₃-C₆ alkylene, C₃-C₆ alkenylene or —(CH₂)₃-cyclopropyl-,        optionally substituted with 1-4 halogen, —OH, or cyano;    -   Q is C₂-C₄ alkyl or C₃-C₆ carbocyclyl optionally substituted        with C₁-C₃ alkyl, halogen, —OH, or cyano;    -   E is C₁-C₃ alkyl or C₂-C₃ alkenyl, optionally substituted with        C₁-C₃ alkyl, halogen, —OH, or cyano;    -   W is H, —O(C₁-C₃)haloalkyl, halogen or cyano; and    -   Z^(2a) is H or C₁-C₃ alkyl, halogen, —OH, or cyano.

In a further embodiment of Formula (IV), {circle around (T)} is C₃-C₆carbocyclylene that is attached to L and to the remainder of thecompound of Formula IV through two adjacent carbons, wherein said C₃-C₆carbocyclene is optionally substituted with C₁-C₄ alkyl or C₁-C₃haloalkyl.

In a further embodiment of Formula (IV), {circle around (T)} is C₃-C₆carbocyclylene that is attached to L and to the remainder of thecompound of Formula IV through two adjacent carbons, wherein the C₃-C₆carbocyclene is optionally substituted with methyl, ethyl ortrifluoromethyl.

In a further embodiment of Formula (IV), {circle around (T)} iscyclopropylene.

In a further embodiment of Formula (IV), {circle around (T)} is C₆-C₈bridged bicyclic carbocyclylene or C₆-C₈ fused bicyclic carbocyclylenethat is attached to L and to the remainder of the compound of Formula IVthrough two adjacent carbons.

In a further embodiment of Formula (IV), L is C₃-C₆ alkylene,substituted with 1-4 halogens. In another embodiment of Formula (IV), Lis C₅ alkylene, substituted with two halogens. In some embodiments, thehalogens are each fluoro.

In a further embodiment of Formula (IV), L is C₃-C₆ alkylene.

In a further embodiment of Formula (IV), L is C₅ alkylene.

In a further embodiment of Formula (IV), Q is t-butyl or C₅-C₆carbocyclyl.

In a further embodiment of Formula (IV), Q is t-butyl.

In a further embodiment of Formula (IV), E is C₁-C₃ alkyl optionallysubstituted with 1-3 halogen atoms.

In a further embodiment of Formula (IV), E is difluoromethyl.

In a further embodiment of Formula (IV), W is hydrogen, —O(C₁-C₃)alkyl,halogen or cyano.

In a further embodiment of Formula (IV), W is methoxy.

In a further embodiment of Formula (IV), Z^(2a) is hydrogen or methyl.

In a further embodiment of Formula (IV), Z^(2a) is methyl.

In one embodiment, a compound of Formula (I):

or a stereoisomer, or a mixture of stereoisomers, or a pharmaceuticallyacceptable salt thereof, is provided, wherein:

-   -   J is J¹, J², J³, J⁴, J⁵, J⁶, J⁷, J⁸ or J⁹;    -   {circle around (T)} is T¹, T², T³, T⁴, T⁵, T⁶, T⁷, T⁸, T⁹, T¹⁰,        T¹¹, T¹², T¹³ or T¹⁴;    -   L is L¹, L², L³, L⁴, L⁵, L⁶, L⁷, L⁸, L⁹ or L¹⁰;    -   X is —O—, —CH₂—, —OC(O)—, —C(O)O—, —C(O)—, —SO₂—, —S(O)—,        —N(R¹⁶)—, —S—, ═N—O— or a bond;    -   A is —C(O)—, —S(O)₂—, a 6-10 membered arylene, 5-10 membered        heteroarylene, or 4-10 membered heterocyclene, wherein any of        said arylene, heterocyclene, or heteroarylene is optionally        substituted with 1-4 Z¹ groups;    -   M is a bond, C₁-C₆ alkylene, —O—, or —N(R¹⁶)—;    -   R¹ is H or F;    -   R³, R⁴, and R⁵ are each independently selected from H or Z¹;    -   Q is Q¹, Q², Q³, Q⁴, Q⁵, Q⁶ or Q⁷;    -   E is E¹, E², E³, E⁴, E⁵, or E⁶;    -   G is —CO₂H, —CONHSO₂Z², tetrazolyl, —CONHP(O)(R¹⁶)₂,        —P(O)(OH)(R¹⁶), and —P(O)(R¹⁶)₂;    -   {circle around (U)} is U¹, U², U³, U⁴, U⁵, U⁶ or U⁷;    -   J¹ is halogen;    -   J² is —OH and R¹ is H;    -   J³ is —NR¹⁷R¹⁸ and R¹ is H;    -   J⁴ is C₁-C₈ alkyl;    -   J⁵ is C₁-C₈ alkyl substituted with 1-4 Z³ groups;    -   J⁶ is C₃-C₈ carbocyclyl optionally substituted with 1-4 Z³        groups;    -   J⁷ is C₆-C₁₀ aryl, 5-10 membered heteroaryl, or 4-10 membered        heterocyclyl optionally substituted with 1-4 Z³ groups;    -   J⁸ is C₁-C₈ alkoxy optionally substituted with 1-4 Z³ groups and        R¹ is H;    -   J⁹ is C₃-C₈ carbocyclyleoxy optionally substituted with 1-4 Z³        groups and R¹ is H;    -   T¹ is C₃-C₈ carbocyclylene that is attached to L and M through        two adjacent carbons;    -   T² is C₃-C₈ carbocyclylene that is attached to L and M through        two adjacent carbons, wherein said carbocyclylene is substituted        with 1-4 C₁-C₈ alkyl groups;    -   T³ is C₃-C₈ carbocyclylene that is attached to L and M through        two adjacent carbons, wherein said carbocyclylene is substituted        with 1-4 halogen atoms and said carbocyclylene is optionally        substituted with 1-4 C₁-C₆ alkyl groups;    -   T⁴ is C₃-C₈ carbocyclylene that is attached to L and M through        two adjacent carbons, wherein said carbocyclylene is optionally        substituted with a C₁-C₈ alkyl group, wherein said alkyl group        is optionally substituted with 1-4 Z³ groups;    -   T⁵ is 4-10 membered heterocyclene that is attached to L and M        through two adjacent carbons;    -   T⁶ is 4-10 membered heterocyclene that is attached to L through        a carbon atom and attached to M through an N atom, wherein said        heterocyclene is optionally substituted with 1-4 Z¹ groups;    -   T⁷ is 4-10 membered heterocyclene that is attached to M through        a carbon atom and attached to L through an N atom, wherein said        heterocyclene is optionally substituted with 1-4 Z¹ groups;    -   T⁸ is 4-10 membered heterocyclene that is attached to L and M        through two adjacent carbons, wherein said heterocyclene is        optionally substituted with 1-4 Z¹ groups;    -   T⁹ is C₅-C₁₂ spiro bicyclic carbocyclylene that is attached to L        and M through two adjacent carbons, wherein said spiro bicyclic        carbocyclylene is optionally substituted with 1-4 Z¹ groups;    -   T¹⁰ is C₅-C₁₂ fused bicyclic carbocyclylene that is attached to        L and M through two adjacent carbons, wherein said fused        bicyclic carbocyclylene is optionally substituted with 1-4 Z¹        groups;    -   T¹¹ is C₅-C₁₂ bridged bicyclic carbocyclylene that is attached        to L and M through two adjacent carbons, wherein said bridged        bicyclic carbocyclylene is optionally substituted with 1-4 Z¹        groups;    -   T¹² is C₄-C₈ carbocyclylene that is attached to L and M through        two non-adjacent carbons, wherein said carbocyclylene is        optionally substituted with 1-4 Z¹ groups;    -   T¹³ is a 5-8 membered fused, bridged, or spiro bicyclic        heterocyclene that is attached to L and M through two adjacent        atoms, wherein said heterocyclene is optionally substituted with        1-4 Z¹ groups;    -   T¹⁴ is C₃-C₈ carbocyclylene that is attached to L and M through        two adjacent carbons, wherein said carbocyclylene is optionally        substituted with 1-4 Z⁴ groups;    -   L¹ is C₁-C₈ alkylene or C₂-C₈ alkenylene;    -   L² is C₁-C₈ alkylene or C₂-C₈ alkenylene wherein said C₁-C₈        alkylene is substituted with 1-4 halogens or said C₂-C₈        alkenylene is substituted with 1-4 halogens;    -   L³ is C₁-C₈ alkylene or C₂-C₈ alkenylene wherein said C₁-C₈        alkylene is substituted with 1-4 Z⁴ groups or said C₂-C₈        alkenylene is substituted with 1-4 Z⁴ groups and wherein each is        optionally substituted with 1-4 halogens;    -   L⁴ is C₁-C₈ alkylene or C₂-C₈ alkenylene substituted with two        geminal C₁-C₄ alkyl groups that come together to form a spiro        C₃-C₈ carbocyclyl group, wherein L⁴ is optionally substituted        with 1-4 Z¹ groups;    -   L⁵ is 2-8 membered heteroalkylene or 4-8 membered        heteroalkenylene that is connected to {circle around (T)} by an        O, S or N atom and said heteroalkylene or heteroalkenylene is        optionally substituted with 1-4 Z³ groups;    -   L⁶ is 2-8 membered heteroalkylene or 5-8 membered        heteroalkenylene that is connected to {circle around (T)} by a        carbon atom and said heteroalkylene or heteroalkenylene is        substituted with 1-4 halogen atoms and is optionally substituted        with 1-4 Z⁴ groups;    -   L⁷ is 2-8 membered heteroalkylene or 4-8 membered        heteroalkenylene that is connected to {circle around (T)} by a        carbon atom and said heteroalkylene or heteroalkenylene is        optionally substituted with 1-4 Z⁴ groups;    -   L⁸ is L^(8A)-L^(8B)-L^(8C) wherein L^(8A) and L^(8C) are each        independently selected from C₁-C₆ alkylene, C₁-C₆        heteroalkylene, C₂-C₆ alkenylene or a bond and L^(8B) is a 3- to        6-membered saturated or unsaturated ring containing 0 to 3        heteroatoms selected from N, O, or S, wherein L^(8A) and L^(8C)        connect to L^(8B) at two different ring atoms and L^(8B) is        optionally substituted with 1-4 Z¹ groups;    -   L⁹ is C₂-C₈ alkynylene optionally substituted with 1-4 Z¹        groups;    -   L¹⁰ is C₁-C₈ alkylene or C₃-C₈ alkenylene substituted with two        geminal Z¹ groups that come together to form a spiro 4-8        membered heterocyclyl group, wherein L¹⁰ is optionally        substituted with 1-4 Z¹ groups;    -   U¹ is C₆-C₁₄ membered arylene optionally substituted with 1-4 W        groups;    -   U² is C₃-C₈ membered carbocyclylene optionally substituted with        1-4 W groups;    -   U³ is 4-14 membered heterocyclene optionally substituted with        1-4 W groups that are located on one or more ring atoms selected        from C or N;    -   U⁴ is 5 or 6 membered monocyclic heteroarylene containing 1, 2        or 3 heteroatoms independently selected from N, O, or S, wherein        said heteroarylene is optionally substituted with 1-4 W groups        that are located on one or more ring atoms selected from C or N;    -   U⁵ is 8, 9 or 10 membered fused bicyclic heteroarylene        containing 1, 2 or 3 heteroatom ring atoms independently        selected from N, O, or S, wherein said heteroarylene is        optionally substituted with 1-4 W groups that are located on one        or more ring atoms selected from C or N;    -   U⁶ is 11-14 membered fused tricyclic heteroarylene containing 1,        2, 3 or 4 heteroatom ring atoms independently selected from N,        O, or S, wherein said heteroarylene is optionally substituted        with 1-4 W groups that are located on one or more ring atoms        selected from C or N;    -   U⁷ is 8-10 membered fused bicyclic heteroarylene containing 4        heteroatom ring atoms independently selected from N, O, or S,        wherein said heteroaryl is optionally substituted with 1-2 W        groups that are located on one or more ring atoms selected from        C or N;    -   W is independently W¹, W², W³, W⁴, W⁵, W⁶ or W⁷;    -   W¹ is oxo, halogen, —OR⁶, C₁-C₆ alkyl, —CN, —CF₃, —SR⁶,        —C(O)₂R⁶, —C(O)N(R⁶)₂, —C(O)R⁶, —N(R⁶)C(O)R⁶, —SO₂(C₁-C₆ alkyl),        —S(O)(C₁-C₆ alkyl), C₃-C₈ carbocyclyl, C₃-C₈ cycloalkoxy, C₁-C₆        haloalkyl, —N(R⁶)₂, —NR⁶(C₁-C₆ alkyl)O(C₁-C₆ alkyl), halo(C₁-C₆        alkoxy), —NR⁶SO₂R⁶, —SO₂N(R⁶)₂, —NHCOOR⁶, —NHCONHR⁶, C₆-C₁₀        aryl, 5-14 membered heteroaryl, 4-10 membered heterocyclyl or        —O(4-10 membered heterocyclyl), wherein said W¹ alkyl,        carbocyclyl, cycloalkoxy, haloalkyl, haloalkoxy, aryl,        heteroaryl, or heterocyclyl is optionally substituted with 1-4        Z^(1c) groups;    -   each R⁶ is independently selected from H, C₆-C₁₀ aryl or C₁-C₆        alkyl, wherein said aryl or alkyl is optionally substituted with        1 to 4 substituents independently selected from halogen atoms,        C₁-C₆ alkyl, C₆-C₁₀ aryl, C₃-C₈ carbocyclyl, 5-14 membered        heteroaryl, 4-10 membered heterocyclyl, halo(C₁-C₆ alkoxy), —OH,        —O(C₁-C₆ alkyl), —SH, —S(C₁-C₆ alkyl), —NH₂, —NH(C₁-C₆ alkyl),        —N(C₁-C₆ alkyl)₂, —C(O)(C₁-C₆ alkyl), —SO₂N(C₁-C₆ alkyl)₂,        —NHCOO(C₁-C₆ alkyl), —NHCO(C₁-C₆ alkyl), —NHCONH(C₁-C₆ alkyl),        —CO₂(C₁-C₆ alkyl), or —C(O)N(C₁-C₆ alkyl)₂;    -   W² is C₁-C₆ alkoxy substituted with a 5-14 membered heteroaryl        or C₆-C₁₀ aryl; wherein said heteroaryl or aryl is substituted        with 1-4 Z¹ groups;    -   W³ is C₂-C₆ alkynyl substituted with an C₆-C₁₀ aryl, C₃-C₈        carbocyclyl, C₁-C₈ alkyl, C₁-C₆ haloalkyl, 4-10 membered        heterocyclyl, or 5-14 membered heteroaryl; wherein said aryl,        carbocyclyl, alkyl, haloalkyl, heterocyclyl, or heteroaryl is        optionally substituted with 1-4 Z¹ groups;    -   W⁴ is —SF₅;    -   W⁵ is —O(C₂-C₆ alkyl)OR²² wherein R²² is an C₆-C₁₀ aryl, 5-14        membered heteroaryl or 4-10 membered heterocyclyl optionally        substituted with 1-4 Z¹ groups;    -   W⁶ is —O(C₂-C₆ alkyl)NR¹⁶R²² wherein R²² is an C₆-C₁₀ aryl, 5-14        membered heteroaryl or 4-10 membered heterocyclyl optionally        substituted with 1-4 Z¹ groups;    -   W⁷ is —O(5-14 membered heteroaryl); wherein said —O(5-14        membered heteroaryl) is optionally substituted with 1-4 Z¹        groups;    -   E¹ is C₂-C₆ alkenyl;    -   E² is C₁-C₆ alkyl;    -   E³ is C₁-C₆ haloalkyl;    -   E⁴ is C₂-C₆ haloalkenyl;    -   E⁵ is C₃-C₆ carbocyclyl;    -   E⁶ is C₁-C₆ alkyl substituted with —OCH₃, —OCD₃, —OCF₃, or        —OCF₂H;    -   Q¹ is H, C₁-C₈ alkyl, C₃-C₈ carbocyclyl, C₆-C₁₀ aryl, 5-6        membered heteroaryl, or 5-6 membered heterocyclyl, wherein when        Q¹ is not H, said Q¹ is optionally substituted with 1-3        substituents independently selected from halogen, —OR⁶, —SR⁶,        —N(R⁶)₂, C₆-C₁₀ aryl, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆        haloalkoxy, —CN, —CF₃, —SO₂(C₁-C₆ alkyl), —S(O)(C₁-C₆ alkyl),        —NR⁶SO₂Z², —SO₂NR¹⁷R¹⁸, —NHCOOR¹⁶, —NHCOZ², —NHCONHR¹⁶, —CO₂R⁶,        —C(O)R⁶, or —CON(R⁶)₂;    -   Q² is C₅-C₁₀ spiro bicyclic carbocyclyl optionally substituted        with 1-4 Z¹ groups;    -   Q³ is C₅-C₁₀ fused bicyclic carbocyclyl optionally substituted        with 1-4 Z¹ groups;    -   Q⁴ is C₅-C₁₀ bridged bicyclic carbocyclyl optionally substituted        with 1-4 Z¹ groups;    -   Q⁵ is 4-membered heterocyclyl having 1 heteroatom selected from        N, O or S wherein Q⁵ is optionally substituted with 1-4 Z³        groups;    -   Q⁶ is C₁-C₈ alkyl, C₃-C₈ carbocyclyl, C₆-C₁₀ aryl, 5-6 membered        heteroaryl, or 5-6 membered heterocyclyl, wherein Q⁶ is        substituted with 1 oxo group and with 0 to 3 substituents        independently selected from halogen, —OR⁶, —SR⁶, —N(R⁶)₂, C₆-C₁₀        aryl, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ haloalkoxy, —NO₂, —CN,        —CF₃, —SO₂(C₁-C₆ alkyl), —S(O)(C₁-C₆ alkyl), —NR⁶SO₂Z²,        —SO₂NR¹⁷R¹⁸, —NHCOOR¹⁶, —NHCOZ², —NHCONHR¹⁶, —CO₂R⁶, —C(O)R⁶, or        —CON(R⁶)₂;    -   Q⁷ is C₃-C₈ carbocyclyl, wherein Q⁷ is substituted with 4-8 F        atoms and each carbon of Q⁷ is substituted with 0-2 F atoms;    -   each Z¹ is independently oxo, halogen, C₁-C₈ alkyl, C₂-C₈        alkenyl, C₂-C₈ alkynyl, C₃-C₈ carbocyclyl, C₅-C₁₀ bicyclic        carbocyclyl, C₁-C₈ haloalkyl, C₆-C₁₀ aryl, 5-14 membered        heteroaryl, 4-10 membered heterocyclyl, —CN, —C(O)R¹⁶,        —C(O)OR¹⁶, —C(O)NR¹⁷R¹⁸, —NR¹⁷R¹⁸, —NR¹⁶C(O)R¹⁶,        —NR¹⁶C(O)NR¹⁷R¹⁸, —NR¹⁶S(O)₂R¹⁶, —NR¹⁶S(O)₂NR¹⁷R¹⁸,        —NR¹⁶S(O)₂OR¹⁶, —OR¹⁶, —OC(O)R¹⁶, —OC(O)NR¹⁷R¹⁸, —SR¹⁶,        —S(O)R¹⁶, —S(O)₂R¹⁶ or —S(O)₂NR¹⁷R¹⁸ wherein any alkyl, alkenyl,        alkynyl, carbocyclyl, aryl, heteroaryl or heterocyclyl of Z¹ is        optionally substituted with 1-4 Z^(1a) groups;    -   each Z^(1a) is independently oxo, halogen, C₂-C₈ alkenyl, C₂-C₈        alkynyl, C₃-C₈ carbocyclyl, C₅-C₁₀ bicyclic carbocyclyl, C₁-C₈        haloalkyl, C₆-C₁₀ aryl, 5-14 membered heteroaryl, 4-10 membered        heterocyclyl, —CN, —C(O)R¹⁶, —C(O)OR¹⁶, —C(O)NR¹⁷R¹⁸, —NR¹⁷R¹⁸,        —NR¹⁶C(O)R¹⁶, —NR¹⁶C(O)OR¹⁶, —NR¹⁶C(O)NR¹⁷R¹⁸, —NR¹⁶S(O)₂R¹⁶,        —NR¹⁶S(O)₂NR¹⁷R¹⁸, —NR¹⁶S(O)₂OR¹⁶, —OR¹⁶, —OC(O)R¹⁶,        —OC(O)NR¹⁷R¹⁸, —SR¹⁶, —S(O)R¹⁶, —S(O)₂R¹⁶ or —S(O)₂NR¹⁷R¹⁸        wherein any alkenyl, alkynyl, carbocyclyl, aryl, heteroaryl or        heterocyclyl of Z^(1a) is optionally substituted with 1-4 Z^(1c)        groups;    -   each R¹⁶ is independently H, C₁-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈        alkynyl, C₃-C₈ carbocyclyl, C₅-C₁₀ bicyclic carbocyclyl, C₆-C₁₀        aryl, 5-14 membered heteroaryl or 4-10 membered heterocyclyl,        wherein any alkyl, alkenyl, alkynyl, carbocyclyl, aryl,        heteroaryl or heterocyclyl of R¹⁶ is optionally substituted with        1-4 Z^(1c) groups;    -   each Z^(1c) is independently oxo, halogen, C₁-C₈ alkyl, C₃-C₈        carbocyclyl, C₅-C₁₀ bicyclic carbocyclyl, C₁-C₈ haloalkyl,        C₆-C₁₀ aryl, 5-14 membered heteroaryl, 4-10 membered        heterocyclyl, —CN, —C(O)(C₁—C₈ alkyl), —C(O)O(C₁-C₈ alkyl),        —C(O)N(C₁-C₈ alkyl)₂, —NH₂, —NH(C₁-C₈ alkyl), —N(C₁-C₈ alkyl)₂,        —NHC(O)O(C₁-C₈ alkyl), —NHC(O)(C₁-C₈ alkyl), —NHC(O)NH(C₁-C₈        alkyl), —OH, —O(C₁-C₈ alkyl), C₃-C₈ cycloalkoxy, C₅-C₁₀ bicyclic        carbocyclyloxy, —S(C₁-C₈ alkyl) or —S(O)₂N(C₁-C₈ alkyl)₂ wherein        any alkyl, carbocyclyl, aryl, heteroaryl, heterocyclyl or        cycloalkoxy portion of Z^(1c) is optionally substituted with 1-4        halogen atoms or C₁-C₆ alkoxy groups;    -   R¹⁷ and R¹⁸ are each independently H, C₁-C₈ alkyl, C₂-C₈        alkenyl, C₂-C₈ alkynyl, C₃-C₈ carbocyclyl, C₅-C₁₀ bicyclic        carbocyclyl, —C(O)R¹⁶, —C(O)OR¹⁶, C₆-C₁₀ aryl, 5-14 membered        heteroaryl or 4-10 membered heterocyclyl, wherein any alkyl,        alkenyl, alkynyl, carbocyclyl, aryl, heteroaryl or heterocyclyl        of R¹⁷ or R¹⁸ is optionally substituted with 1-4 Z^(1c) groups,        or R¹⁷ and R¹⁸ together with the nitrogen to which they are        attached form a 4-7 membered heterocyclyl group, wherein said        4-7 membered heterocyclyl group is optionally substituted with        1-4 Z^(1c) groups;    -   each Z² is independently C₁-C₈ alkyl, C₃-C₈ carbocyclyl, C₅-C₁₀        bicyclic carbocyclyl, C₆-C₁₀ aryl, 5-14 membered heteroaryl,        4-10 membered heterocyclyl, —NR¹⁷R¹⁸ or —OR¹⁶ wherein any alkyl,        carbocyclyl, aryl, heteroaryl or heterocyclyl portion of Z² is        optionally substituted with 1-4 Z^(2a) groups;    -   each Z^(2a) is independently oxo, halogen, C₁-C₈ alkyl, C₂-C₈        alkynyl, C₃-C₈ carbocyclyl, C₅-C₁₀ bicyclic carbocyclyl, C₁-C₈        haloalkyl, C₆-C₁₀ aryl, 5-14 membered heteroaryl, 4-10 membered        heterocyclyl, —(C₂-C₈ alkynyl)aryl, —(C₂-C₈ alkynyl)heteroaryl,        —CN, —C(O)(C₁-C₆ alkyl), —C(O)O(C₁-C₆ alkyl), —C(O)N(C₁-C₆        alkyl)₂, —NH₂, —NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)₂,        —NHC(O)O(C₁-C₆ alkyl), —NHC(O)(C₁-C₆ alkyl), —NHC(O)NH(C₁-C₆        alkyl), —OH, —O(C₁-C₆ alkyl), halo(C₁-C₆ alkoxy), C₃-C₈        cycloalkoxy, —S(C₁-C₆ alkyl), or —SO₂N(C₁-C₆ alkyl)₂; wherein        any alkyl, alkynyl, carbocyclyl, cycloalkoxy, aryl, heteroaryl        or heterocyclyl portions of Z^(2a) is optionally substituted        with 1-4 halogen or C₁-C₆ alkoxy groups;    -   each Z³ is independently oxo, halogen, C₂-C₈ alkenyl, C₂-C₈        alkynyl, C₃-C₈ carbocyclyl, C₅-C₁₀ bicyclic carbocyclyl, C₁-C₈        haloalkyl, C₆-C₁₀ aryl, 5-14 membered heteroaryl, 4-10 membered        heterocyclyl, —CN, —C(O)OR¹⁶, —C(O)NR¹⁷R¹⁸, —NR¹⁷R¹⁸,        —NR¹⁶C(O)NR¹⁷R¹⁸, —OR¹⁶, —SR¹⁶ or —SO₂R¹⁶; wherein any alkenyl,        alkynyl, carbocyclyl, aryl, heteroaryl or heterocyclyl portions        of Z³ is optionally substituted with 1-4 halogen; and    -   each Z⁴ is independently oxo, C₂-C₈ alkenyl, C₂-C₈ alkynyl,        C₃-C₈ carbocyclyl, C₅-C₁₀ bicyclic carbocyclyl, C₁-C₈ haloalkyl,        C₆-C₁₀ aryl, 5-14 membered heteroaryl, 4-10 membered        heterocyclyl, —CN, —C(O)OR¹⁶, —C(O)NR¹⁷R¹⁸, —NR¹⁷R¹⁸,        —NR¹⁶C(O)NR¹⁷R¹⁸, —OR¹⁶, —SR¹⁶ or —SO₂R¹⁶, wherein any alkenyl,        alkynyl, carbocyclyl, aryl, heteroaryl or heterocyclyl portions        of Z⁴ is optionally substituted with 1-4 halogen.

In another embodiment, a compound of Formula (II):

or a stereoisomer, or a mixture of stereoisomers, or a pharmaceuticallyacceptable salt thereof, is provided, wherein:

-   -   M is —O—;    -   J is J¹, J², J³, J⁴, J⁵, J⁶, J⁷, J⁸ or J⁹;    -   {circle around (T)} is T¹, T², T³, T⁴, T⁵, T⁷, T⁸, T⁹, T¹, T¹¹,        T¹², T¹³ or T¹⁴;    -   L is L¹, L², L³, L⁴, L⁵, L⁶, L⁷, L⁸, L⁹ or L¹⁰;    -   R¹ is H or F;    -   Q is Q¹, Q², Q³, Q⁴, Q⁵, Q⁶ or Q⁷;    -   E is E¹, E², E³, E⁴, E⁵, or E6;    -   {circle around (U)} is U¹, U², U³, U⁴, U⁵, U⁶ or U⁷;    -   J¹ is halogen;    -   J² is —OH and R¹ is H;    -   J³ is —NR¹⁷R¹⁸ and R¹ is H;    -   J⁴ is C₁-C₈ alkyl;    -   J⁵ is C₁-C₈ alkyl optionally substituted with 1-4 Z³ groups;    -   J⁶ is C₃-C₈ carbocyclyl optionally substituted with 1-4 Z³        groups;    -   J⁷ is C₆-C₁₀ aryl, 5-14 membered heteroaryl, or 4-10 membered        heterocyclyl, any of which are optionally substituted with 1-4        Z³ groups;    -   J⁸ is C₁-C₈ alkoxy optionally substituted with 1-4 Z³ groups and        R¹ is H;    -   J⁹ is C₃-C₈ carbocyclyloxy optionally substituted with 1-4 Z³        groups and R¹ is H;    -   T¹ is C₃-C₈ carbocyclylene that is attached to L and M through        two adjacent carbons;    -   T² is C₃-C₈ carbocyclylene that is attached to L and M through        two adjacent carbons, wherein said carbocyclylene is optionally        substituted with 1-4 C₁-C₈ alkyl groups;    -   T³ is C₃-C₈ carbocyclylene that is attached to L and M through        two adjacent carbons, wherein said carbocyclylene is optionally        substituted with 1-4 halogen atoms and said carbocyclylene is        optionally substituted with 1-4 C₁-C₆ alkyl groups;    -   T⁴ is C₃-C₈ carbocyclylene that is attached to L and M through        two adjacent carbons, wherein said carbocyclylene is optionally        substituted with a C₁-C₈ alkyl group, wherein said alkyl group        is optionally substituted with 1-4 Z³ groups;    -   T⁵ is 4-10 membered heterocyclene that is attached to L and M        through two adjacent carbons;    -   T⁷ is 4-10 membered heterocyclene that is attached to M through        a carbon atom and attached to L through a N atom, wherein said        heterocyclene is optionally substituted with 1-4 Z¹ groups;    -   T⁸ is 4-10 membered heterocyclene that is attached to L and M        through two adjacent carbons, wherein said heterocyclene is        optionally substituted with 1-4 Z¹ groups;    -   T⁹ is C₅-C₁₂ spiro bicyclic carbocyclylene that is attached to L        and M through two adjacent carbons, wherein said spiro bicyclic        carbocyclylene is optionally substituted with 1-4 Z¹ groups;    -   T¹⁰ is C₅-C₁₂ fused bicyclic carbocyclylene that is attached to        L and M through two adjacent carbons, wherein said fused        bicyclic carbocyclylene is optionally substituted with 1-4 Z¹        groups;    -   T¹¹ is C₅-C₁₂ bridged bicyclic carbocyclylene that is attached        to L and M through two adjacent carbons, wherein said bridged        bicyclic carbocyclylene is optionally substituted with 1-4 Z¹        groups;    -   T¹² is C₄-C₈ carbocyclylene that is attached to L and M through        two non-adjacent carbons, wherein said carbocyclylene is        optionally substituted with 1-4 Z¹ groups;    -   T¹³ is a 5-8 membered fused, bridged, or spiro bicyclic        heterocyclene that is attached to L and M through two adjacent        atoms, wherein said heterocyclene is optionally substituted with        1-4 Z¹ groups;    -   T¹⁴ is C₃-C₈ carbocyclylene that is attached to L and M through        two adjacent carbons, wherein said carbocyclylene is optionally        substituted with 1-4 Z⁴ groups;    -   L¹ is C₁-C₈ alkylene or C₂-C₈ alkenylene;    -   L² is C₁-C₈ alkylene or C₂-C₈ alkenylene wherein said C₁-C₈        alkylene is substituted with 1-4 halogens or said C₂-C₈        alkenylene is substituted with 1-4 halogens;    -   L³ is C₁-C₈ alkylene or C₂-C₈ alkenylene wherein said C₁-C₈        alkylene is substituted with 1-4 Z⁴ groups or said C₂-C₈        alkenylene is substituted with 1-4 Z⁴ groups and wherein each is        optionally substituted with 1-4 halogens;    -   L⁴ is C₁-C₈ alkylene or C₂-C₈ alkenylene substituted with two        geminal C₁-C₄ alkyl groups that come together to form a spiro        C₃-C₈ carbocyclyl group, wherein L⁴ is optionally substituted        with 1-4 Z¹ groups;    -   L⁵ is 2-8 membered heteroalkylene or 4-8 membered        heteroalkenylene that is connected to {circle around (T)} by an        O, S or N atom and said heteroalkylene or heteroalkenylene is        optionally substituted with 1-4 Z³ groups;    -   L⁶ is 2-8 membered heteroalkylene or 5-8 membered        heteroalkenylene that is connected to {circle around (T)} by a        carbon atom and said heteroalkylene or heteroalkenylene is        substituted with 1-4 halogen atoms and is optionally substituted        with 1-4 Z⁴ groups;    -   L⁷ is 2-8 membered heteroalkylene or 4-8 membered        heteroalkenylene that is connected to {circle around (T)} by a        carbon atom and said heteroalkylene or heteroalkenylene is        optionally substituted with 1-4 Z⁴ groups;    -   L⁸ is L^(8A)-L^(8B)-L⁸ wherein L^(8A) and L^(8C) are each        independently selected from C₁-C₆ alkylene, C₁-C₆        heteroalkylene, C₂-C₆ alkenylene or a bond and L^(8B) is a 3- to        6-membered saturated or unsaturated ring containing 0 to 3        heteroatoms selected from N, O, or S, wherein L^(8A) and L^(8C)        connect to L^(8B) at two different ring atoms and L^(8B) is        optionally substituted with 1-4 Z¹ groups;    -   L⁹ is C₂-C₈ alkynylene optionally substituted with 1-4 Z¹        groups;    -   L¹⁰ is C₁-C₈ alkylene or C₃-C₈ alkenylene substituted with two        geminal Z¹ groups that come together to form a spiro 4-8        membered heterocyclyl group, wherein L¹⁰ is optionally        substituted with 1-4 Z¹ groups;    -   U¹ is C₆-C₁₄ membered arylene optionally substituted with 1-4 W        groups;    -   each U² is C₃-C₈ membered carbocyclylene optionally substituted        1-4 W groups;    -   each U³ is 4-14 membered heterocyclene optionally substituted        with 1-4 W groups that are located on one or more ring atoms        selected from C or N;    -   U⁴ is 5 or 6 membered monocyclic heteroarylene containing 1, 2        or 3 heteroatoms independently selected from N, O, or S, wherein        said heteroarylene is optionally substituted with 1-4 W groups        that are located on one or more ring atoms selected from C or N;    -   U⁵ is 8, 9 or 10 membered fused bicyclic heteroarylene        containing 1, 2 or 3 heteroatom ring atoms independently        selected from N, O, or S, wherein said heteroarylene is        optionally substituted with 1-4 W groups that are located on one        or more ring atoms selected from C or N;    -   U⁶ is 11-14 membered fused tricyclic heteroarylene containing 1,        2, 3 or 4 heteroatom ring atoms independently selected from N,        O, or S, wherein said heteroarylene is optionally substituted        with 1-4 W groups that are located on one or more ring atoms        selected from C or N;    -   U⁷ is 8-10 membered fused bicyclic heteroarylene containing 4        heteroatom ring atoms independently selected from N, O, or S,        wherein said heteroaryl is optionally substituted with 1-2 W        groups that are located on one or more ring atoms selected from        C or N;    -   each W is independently W¹, W², W³, W⁴, W⁵, W⁶ or W⁷;    -   each W¹ is oxo, halogen, —OR⁶, C₁-C₆ alkyl, —CN, —CF₃, —SR⁶,        —C(O)₂R⁶, —C(O)N(R⁶)₂, —C(O)R⁶, —N(R⁶)C(O)R⁶, —SO₂(C₁-C₆ alkyl),        —S(O)(C₁-C₆ alkyl), C₃-C₈ carbocyclyl, C₃-C₈ cycloalkoxy, C₁-C₆        haloalkyl, —N(R⁶)₂, —NR⁶(C₁-C₆ alkyl)O(C₁-C₆ alkyl), halo(C₁-C₆        alkoxy), —NR⁶SO₂R⁶, —SO₂N(R⁶)₂, —NHCOOR⁶, —NHCONHR⁶, C₆-C₁₀        aryl, 5-14 membered heteroaryl, 4-10 membered heterocyclyl or        —O(4-10 membered heterocyclyl), wherein said W¹ alkyl,        carbocyclyl, cycloalkoxy, haloalkyl, haloalkoxy, aryl,        heteroaryl, or heterocyclyl is optionally substituted with 1-4        Z^(1c) groups;    -   each R⁶ is independently selected from H, C₆-C₁₀ aryl or C₁-C₆        alkyl, wherein said aryl or alkyl is optionally substituted with        1 to 4 substituents independently selected from halogen atoms,        C₁-C₆ alkyl, C₆-C₁₀ aryl, C₃-C₈ carbocyclyl, 5-14 membered        heteroaryl, 4-10 membered heterocyclyl, halo(C₁-C₆ alkoxy), —OH,        —O(C₁-C₆ alkyl), —SH, —S(C₁-C₆ alkyl), —NH₂, —NH(C₁-C₆ alkyl),        —N(C₁-C₆ alkyl)₂, —C(O)(C₁-C₆ alkyl), —SO₂N(C₁-C₆ alkyl)₂,        —NHCOO(C₁-C₆ alkyl), —NHCO(C₁-C₆ alkyl), —NHCONH(C₁-C₆ alkyl),        —CO₂(C₁-C₆ alkyl), or —C(O)N(C₁-C₆ alkyl)₂;    -   each W² is C₁-C₆ alkoxy substituted with a 5-14 membered        heteroaryl or C₆-C₁₀ aryl; wherein said heteroaryl or aryl is        substituted with 1-4 Z¹C groups;    -   each W³ is C₂-C₆ alkynyl substituted with an C₆-C₁₀ aryl, C₃-C₈        carbocyclyl, C₁-C₈ alkyl, C₁-C₆ haloalkyl, 4-10 membered        heterocyclyl, or 5-14 membered heteroaryl; wherein said aryl,        carbocyclyl, alkyl, haloalkyl, heterocyclyl, or heteroaryl is        optionally substituted with 1-4 Z¹ groups;    -   each W⁴ is —SF₅;    -   each W⁵ is —O(C₂-C₆ alkyl)OR²² wherein R²² is an C₆-C₁₀ aryl,        5-14 membered heteroaryl or 4-10 membered heterocyclyl        optionally substituted with 1-4 Z¹ groups;    -   each W⁶ is —O(C₂-C₆ alkyl)NR¹⁶R²² wherein R²² is an C₆-C₁₀ aryl,        5-14 membered heteroaryl or 4-10 membered heterocyclyl        optionally substituted with 1-4 Z¹ groups;    -   each W⁷ is —O(5-14 membered heteroaryl); wherein said —O(5-14        membered heteroaryl) is optionally substituted with 1-4 Z¹        groups and 2 adjacent substituents of said —O(5-14 membered        heteroaryl) may be taken together to form a 3- to 6-membered        cyclic ring containing 0 to 3 heteroatoms independently selected        from N, O, or S;    -   E¹ is C₂-C₆ alkenyl;    -   E² is O₁—C₆ alkyl;    -   E³ is C₁-C₆ haloalkyl;    -   E⁴ is C₂-C₆ haloalkenyl;    -   E⁵ is C₃-C₆ carbocyclyl;    -   E⁶ is C₁-C₆ alkyl optionally substituted with —OCH₃, —OCD₃,        —OCF₃, or —OCF₂H;    -   Q¹ is selected from H, C₁-C₈ alkyl, C₃-C₈ carbocyclyl, C₆-C₁₀        aryl, 5-6 membered heteroaryl, or 5-6 membered heterocyclyl        groups, wherein when Q¹ is not H, said Q¹ is optionally        substituted with 1-4 substituents independently selected from        halogen, —OR⁶, —SR⁶, —N(R⁶)₂, C₆-C₁₀ aryl, C₁-C₆ alkyl, C₁-C₆        haloalkyl, C₁-C₆ haloalkoxy, —NO₂, —CN, —CF₃, —SO₂(C₁-C₆ alkyl),        —S(O)(C₁-C₆ alkyl), —NR⁶SO₂Z², —SO₂NR¹⁷R¹⁸, —NHCOOR¹⁶, —NHCOZ²,        —NHCONHR¹⁶, —CO₂R⁶, —C(O)R⁶, and —CON(R⁶)₂;    -   Q² is C₅-C₁₀ spiro bicyclic carbocyclyl optionally substituted        with 1-4 Z¹ groups;    -   Q³ is C₅-C₁₀ fused bicyclic carbocyclyl optionally substituted        with 1-4 Z¹ groups;    -   Q⁴ is C₅-C₁₀ bridged bicyclic carbocyclyl optionally substituted        with 1-4 Z¹ groups;    -   Q⁵ is 4-membered heterocyclyl having 1 heteroatom selected from        N, O or S wherein Q⁵ is optionally substituted with 1-4 Z³        groups;    -   Q⁶ is C₁-C₈ alkyl, C₃-C₈ carbocyclyl, C₆-C₁₀ aryl, 5-6 membered        heteroaryl, or 5-6 membered heterocyclyl, wherein Q⁶ is        substituted with 1 oxo group and with 0 to 3 substituents        independently selected from halogen, —OR⁶, —SR⁶, —N(R⁶)₂, C₆-C₁₀        aryl, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ haloalkoxy, —NO₂, —CN,        —CF₃, —SO₂(C₁-C₆ alkyl), —S(O)(C₁-C₆ alkyl), —NR⁶SO₂Z²,        —SO₂NR¹⁷R¹⁸, —NHCOOR¹⁶, —NHCOZ², —NHCONHR¹⁶, —CO₂R⁶, —C(O)R⁶, or        —CON(R⁶)₂;    -   Q⁷ is C₃-C₈ carbocyclyl, wherein Q⁷ is substituted with 4-8 F        atoms and each carbon of Q⁷ is substituted with 0-2 F atoms;    -   each Z¹ is independently oxo, halogen, C₁-C₈ alkyl, C₂-C₈        alkenyl, C₂-C₈ alkynyl, C₃-C₈ carbocyclyl, C₅-C₁₀ bicyclic        carbocyclyl, C₁-C₈ haloalkyl, C₆-C₁₀ aryl, 5-14 membered        heteroaryl, 4-10 membered heterocyclyl, —CN, —C(O)R¹⁶,        —C(O)OR¹⁶, —C(O)NR¹⁷R¹⁸, —NR¹⁷R¹⁸, —NR¹⁶C(O)R¹⁶,        —NR¹⁶C(O)NR¹⁷R¹⁸, —NR¹⁶S(O)₂R¹⁶, —NR¹⁶S(O)₂NR¹⁷R¹⁸,        —NR¹⁶S(O)₂OR¹⁶, —OR¹⁶, —OC(O)R¹⁶, —OC(O)NR¹⁷R¹⁸, —SR¹⁶,        —S(O)R¹⁶, —S(O)₂R¹⁶ or —S(O)₂NR¹⁷R¹⁸ wherein any alkyl, alkenyl,        alkynyl, carbocyclyl, aryl, heteroaryl or heterocyclyl of Z¹ is        optionally substituted with 1-4 Z^(1a) groups;    -   each Z^(1a) is independently oxo, halogen, C₂-C₈ alkenyl, C₂-C₈        alkynyl, C₃-C₈ carbocyclyl, C₅-C₁₀ bicyclic carbocyclyl, C₁-C₈        haloalkyl, C₆-C₁₀ aryl, 5-14 membered heteroaryl, 4-10 membered        heterocyclyl, —CN, —C(O)R¹⁶, —C(O)OR¹⁶, —C(O)NR¹⁷R¹⁸, —NR¹⁷R¹⁸,        —NR¹⁶C(O)R¹⁶, —NR¹⁶C(O)OR¹⁶, —NR¹⁶C(O)NR¹⁷R¹⁸, —NR¹⁶S(O)₂R¹⁶,        —NR¹⁶S(O)₂NR¹⁷R¹⁸, —NR¹⁶S(O)₂OR¹⁶, —OR¹⁶, —OC(O)R¹⁶,        —OC(O)NR¹⁷R¹⁸, —SR¹⁶, —S(O)R¹⁶, —S(O)₂R¹⁶ or —S(O)₂NR¹⁷R¹⁸        wherein any alkenyl, alkynyl, carbocyclyl, aryl, heteroaryl or        heterocyclyl of Z^(1a) is optionally substituted with 1-4 Z^(1c)        groups;    -   each R¹⁶ is independently H, C₁-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈        alkynyl, C₃-C₈ carbocyclyl, C₅-C₁₀ bicyclic carbocyclyl, C₆-C₁₀        aryl, 5-14 membered heteroaryl or 4-10 membered heterocyclyl,        wherein any alkyl, alkenyl, alkynyl, carbocyclyl, aryl,        heteroaryl or heterocyclyl of R¹⁶ is optionally substituted with        1-4 Z^(1c) groups;    -   each Z^(1c) is independently oxo, halogen, C₁-C₈ alkyl, C₃-C₈        carbocyclyl, C₅-C₁₀ bicyclic carbocyclyl, C₁-C₈ haloalkyl,        C₆-C₁₀ aryl, 5-14 membered heteroaryl, 4-10 membered        heterocyclyl, —CN, —C(O)(C₁-C₈ alkyl), —C(O)O(C₁-C₈ alkyl),        —C(O)N(C₁-C₈ alkyl)₂, —NH₂, —NH(C₁-C₈ alkyl), —N(C₁-C₈ alkyl)₂,        —NHC(O)O(C₁-C₈ alkyl), —NHC(O)(C₁-C₈ alkyl), —NHC(O)NH(C₁-C₈        alkyl), —OH, —O(C₁-C₈ alkyl), C₃-C₈ cycloalkoxy, C₅-C₁₀ bicyclic        carbocyclyloxy, —S(C₁-C₈ alkyl) or —S(O)₂N(C₁-C₈ alkyl)₂ wherein        any alkyl, carbocyclyl, aryl, heteroaryl, heterocyclyl or        cycloalkoxy portion of Z^(1c) is optionally substituted with 1-4        halogen atoms or C₁-C₆ alkoxy groups;    -   R¹⁷ and R¹⁸ are each independently H, C₁-C₈ alkyl, C₂-C₈        alkenyl, C₂-C₈ alkynyl, C₃-C₈ carbocyclyl, C₅-C₁₀ bicyclic        carbocyclyl, —C(O)R¹⁶, —C(O)OR¹⁶, C₆-C₁₀ aryl, 5-14 membered        heteroaryl or 4-10 membered heterocyclyl, wherein any alkyl,        alkenyl, alkynyl, carbocyclyl, aryl, heteroaryl or heterocyclyl        of R¹⁷ or R¹⁸ is optionally substituted with 1-4 Z^(1c) groups,        or R¹⁷ and R¹⁸ together with the nitrogen to which they are        attached form a 4-7 membered heterocyclyl group, wherein said        4-7 membered heterocyclyl group is optionally substituted with        1-4 Z^(1c) groups;    -   each Z² is independently C₁-C₈ alkyl, C₃-C₈ carbocyclyl, C₅-C₁₀        bicyclic carbocyclyl, C₆-C₁₀ aryl, 5-14 membered heteroaryl,        4-10 membered heterocyclyl, —NR¹⁷R¹⁸ or —OR¹⁶ wherein any alkyl,        carbocyclyl, aryl, heteroaryl or heterocyclyl portion of Z² is        optionally substituted with 1-4 Z^(2a) groups;    -   each Z^(2a) is independently oxo, halogen, C₁-C₈ alkyl, C₂-C₈        alkynyl, C₃-C₈ carbocyclyl, C₅-C₁₀ bicyclic carbocyclyl, C₁-C₈        haloalkyl, C₆-C₁₀ aryl, 5-14 membered heteroaryl, 4-10 membered        heterocyclyl, —(C₂-C₈ alkynyl)aryl, —(C₂-C₈ alkynyl)heteroaryl,        —CN, —C(O)(C₁-C₆ alkyl), —C(O)O(C₁-C₆ alkyl), —C(O)N(C₁-C₆        alkyl)₂, —NH₂, —NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)₂,        —NHC(O)O(C₁-C₆ alkyl), —NHC(O)(C₁-C₆ alkyl), —NHC(O)NH(C₁-C₆        alkyl), —OH, —O(C₁-C₆ alkyl), halo(C₁-C₆ alkoxy), C₃-C₈        cycloalkoxy, —S(C₁-C₆ alkyl), or —SO₂N(C₁-C₆ alkyl)₂; wherein        any alkyl, alkynyl, carbocyclyl, cycloalkoxy, aryl, heteroaryl        or heterocyclyl portions of Z^(2a) is optionally substituted        with 1-4 halogen or C₁-C₆ alkoxy groups;    -   each Z³ is independently oxo, halogen, C₂-C₈ alkenyl, C₂-C₈        alkynyl, C₃-C₈ carbocyclyl, C₅-C₁₀ bicyclic carbocyclyl, C₁-C₈        haloalkyl, C₆-C₁₀ aryl, 5-14 membered heteroaryl, 4-10 membered        heterocyclyl, —CN, —C(O)OR¹⁶, —C(O)NR¹⁷R¹⁸, —NR¹⁷R¹⁸,        —NR¹⁶C(O)NR¹⁷R¹⁸, —OR¹⁶, —SR¹⁶ or —SO₂R¹⁶; wherein any alkenyl,        alkynyl, carbocyclyl, aryl, heteroaryl or heterocyclyl portions        of Z³ is optionally substituted with 1-4 halogen; and    -   each Z⁴ is independently oxo, C₂-C₈ alkenyl, C₂-C₈ alkynyl,        C₃-C₈ carbocyclyl, C₅-C₁₀ bicyclic carbocyclyl, C₁-C₈ haloalkyl,        C₈-C₁₀ aryl, 5-14 membered heteroaryl, 4-10 membered        heterocyclyl, —CN, —C(O)OR¹⁶, —C(O)NR¹⁷R¹⁸, —NR¹⁷R¹⁸,        —NR¹⁶C(O)NR¹⁷R¹⁸, —OR¹⁶, —SR¹⁶ or —SO₂R¹⁶, wherein any alkenyl,        alkynyl, carbocyclyl, aryl, heteroaryl or heterocyclyl portions        of Z⁴ is optionally substituted with 1-4 halogen.

In a further embodiment a compound of Formula (III):

or a stereoisomer, or a mixture of stereoisomers, or a pharmaceuticallyacceptable salt thereof, is provided, wherein:

-   -   M is —O—;    -   J is J¹, J², J³, J⁴, J⁵, J⁶, J⁷, J⁸ or J⁹;    -   {circle around (T)} is T¹, T², T³, T⁴, T⁵, T⁷, T⁸, T⁹, T¹⁰, T¹¹,        T¹², T¹³ or T¹⁴;    -   L is L¹, L², L³, L⁴, L⁵, L⁶, L⁷, L⁸, L⁹ or L¹⁰;    -   Q is Q¹, Q², Q³, Q⁴, Q⁵ or Q⁷;    -   E is E¹, E², E³, or E4;    -   {circle around (U)} is selected from U¹, U³, U⁴, U⁵, U⁶ or U⁷;    -   J¹ is halogen;    -   J² is —OH;    -   J³ is —NR¹⁷R¹⁸;    -   J⁴ is C₁-C₈ alkyl;    -   J⁵ is C₁-C₈ alkyl substituted with 1-4 Z³ groups;    -   J⁶ is C₃-C₈ carbocyclyl optionally substituted with 1-4 Z³        groups;    -   J⁷ is C₆-C₁₀ aryl, 5-14 membered heteroaryl, or 4-10 membered        heterocyclyl any of which groups are optionally substituted with        1-4 Z³ groups;    -   J⁸ is C₁-C₈ alkoxy optionally substituted with 1-4 Z³ groups;    -   J⁹ is C₃-C₈ carbocyclyleoxy optionally substituted with 1-4 Z³        groups;    -   T¹ is C₃-C₈ carbocyclylene attached to L and M through two        adjacent carbons;    -   T² is C₃-C₈ carbocyclylene attached to L and M through two        adjacent carbons, wherein said carbocyclylene is substituted        with 1-4 C₁-C₈ alkyl groups;    -   T³ is C₃-C₈ carbocyclylene attached to L and M through two        adjacent carbons, wherein said carbocyclylene is substituted        with 1-4 halogen atoms and said carbocyclylene is optionally        substituted with 1-4 C₁-C₆ alkyl groups;    -   T⁴ is C₃-C₈ carbocyclylene that is attached to L and M through        two adjacent carbons, wherein said carbocyclylene is substituted        with a C₁-C₈ alkyl group, wherein said alkyl group is        substituted with 1-4 Z³ groups;    -   T⁵ is 4-10 membered heterocyclene that is attached to L and M        through two adjacent carbons;    -   T⁷ is 4-10 membered heterocyclene that is attached to M through        a carbon atom and attached to L through a N atom, wherein said        heterocyclene is optionally substituted with 1-4 Z¹ groups;    -   T⁸ is 4-10 membered heterocyclene that is attached to L and M        through two adjacent carbons, wherein said heterocyclene is        substituted with 1-4 Z¹ groups;    -   T⁹ is C₅-C₁₂ spiro bicyclic carbocyclylene that is attached to L        and M through two adjacent carbons, wherein said spiro bicyclic        carbocyclylene is optionally substituted with 1-4 Z¹ groups;    -   T¹⁰ is C₅-C₁₂ fused bicyclic carbocyclylene that is attached to        L and M through two adjacent carbons, wherein said fused        bicyclic carbocyclylene is optionally substituted with 1-4 Z¹        groups;    -   T¹¹ is C₅-C₁₂ bridged bicyclic carbocyclylene that is attached        to L and M through two adjacent carbons, wherein said bridged        bicyclic carbocyclylene is optionally substituted with 1-4 Z¹        groups;    -   T¹² is C₄-C₈ carbocyclylene that is attached to L and M through        two non-adjacent carbons, wherein said carbocyclylene is        optionally substituted with 1-4 Z¹ groups;    -   T¹³ is a 5-8 membered fused, bridged, or spiro bicyclic        heterocyclene that is attached to L and M through two adjacent        atoms, wherein said heterocyclene is optionally substituted with        1-4 Z¹ groups;    -   T¹⁴ is C₃-C₈ carbocyclylene that is attached to L and M through        two adjacent carbons, wherein said carbocyclylene is substituted        with 1-4 Z⁴ groups;    -   L¹ is C₁-C₈ alkylene or C₂-C₈ alkenylene;    -   L² is C₁-C₈ alkylene or C₂-C₈ alkenylene wherein said C₁-C₈        alkylene or said C₂-C₈ alkenylene is substituted with 1-4        halogens;    -   L³ is C₁-C₈ alkylene or C₂-C₈ alkenylene wherein said C₁-C₈        alkylene or said C₂-C₈ alkenylene and wherein said C₁-C₈        alkylene or said C₂-C₈ alkenylene is optionally substituted with        1-4 halogens;    -   L⁴ is C₁-C₈ alkylene or C₂-C₈ alkenylene substituted with two        geminal C₁-C₄ alkyl groups that come together to form a spiro        C₃-C₈ carbocyclyl group, wherein L⁴ is optionally substituted        with 1-4 Z¹ groups;    -   L⁵ is 2-8 membered heteroalkylene or 4-8 membered        heteroalkenylene that is connected to {circle around (T)} by an        O, S or N atom and said heteroalkylene or heteroalkenylene is        optionally substituted with 1-4 Z³ groups;    -   L⁶ is 2-8 membered heteroalkylene or 5-8 membered        heteroalkenylene that is connected to {circle around (T)} by a        carbon atom and said heteroalkylene or heteroalkenylene is        substituted with 1-4 halogen atoms and is optionally substituted        with 1-4 Z⁴ groups;    -   L⁷ is 2-8 membered heteroalkylene or 4-8 membered        heteroalkenylene that is connected to {circle around (T)} by a        carbon atom and said heteroalkylene or heteroalkenylene is        optionally substituted with 1-4 Z⁴ groups;    -   L⁸ is L^(8A)-L^(8B)-L⁸ wherein L^(8A) and L^(8C) are each        independently C₁-C₆ alkylene, C₁-C₆ heteroalkylene, C₂-C₆        alkenylene or a bond and L^(8B) is a 3- to 6-membered saturated        or unsaturated ring containing 0 to 3 heteroatoms selected from        N, O, or S, wherein L^(8A) and L^(8C) connect to L^(8B) at two        different ring atoms and L^(8B) is optionally substituted with        1-4 Z¹ groups;    -   L⁹ is C₂-C₈ alkynylene optionally substituted with 1-4 Z¹        groups;    -   L¹⁰ is C₁-C₈ alkylene or C₃-C₈ alkenylene substituted with two        geminal Z¹ groups that come together to form a spiro 4-8        membered heterocyclyl group, wherein L¹⁰ is optionally        substituted with 1-4 Z¹ groups;    -   U¹ is a C₆-C₁₄ membered arylene optionally substituted with 1-4        W groups;    -   U³ is a 4-14 membered heterocyclene optionally substituted with        1-4 W groups that are located on one or more ring atoms selected        from C or N;    -   U⁴ is a 5 or 6 membered monocyclic heteroarylene containing 1, 2        or 3 heteroatoms independently selected from N, O, or S, wherein        said heteroarylene is optionally substituted with 1-4 W groups        that are located on one or more ring atoms selected from C or N;    -   U⁵ is a 8, 9 or 10 membered fused bicyclic heteroarylene        containing 1, 2 or 3 heteroatom ring atoms independently        selected from N, O, or S, wherein said heteroarylene is        optionally substituted with 1-4 W groups that are located on one        or more ring atoms selected from C or N;    -   U⁶ is a 11-14 membered fused tricyclic heteroarylene containing        1, 2, 3 or 4 heteroatom ring atoms independently selected from        N, O, or S, wherein said heteroarylene is optionally substituted        with 1-4 W groups that are located on one or more ring atoms        selected from C or N;    -   U⁷ is a 8-10 membered fused bicyclic heteroarylene containing 4        heteroatom ring atoms independently selected from N, O, or S,        wherein said heteroaryl is optionally substituted with 1-2 W        groups that are located on one or more ring atoms selected from        C or N;    -   each W is independently W¹, W², W³, W⁴, W⁵, W⁶ or W⁷;    -   each W¹ is independently oxo, halogen, —OR⁶, C₁-C₆ alkyl, —CN,        —CF₃, —SR⁶, —C(O)₂R⁶, —C(O)N(R⁶)₂, —C(O)R⁶, —N(R⁶)C(O)R⁶,        —SO₂(C₁-C₆ alkyl), —S(O)(C₁-C₆ alkyl), C₃-C₈ carbocyclyl, C₃-C₈        cycloalkoxy, C₁-C₆ haloalkyl, —N(R⁶)₂, —NR⁶(C₁-C₆ alkyl)O(C₁-C₆        alkyl), halo(C₁-C₆ alkoxy), —NR⁶SO₂R⁶, —SO₂N(R⁶)₂, —NHCOOR⁶,        —NHCONHR⁶, C₆-C₁₀ aryl, 5-14 membered heteroaryl, 4-10 membered        heterocyclyl or —O(4-10 membered heterocyclyl), wherein said W¹        alkyl, carbocyclyl, cycloalkoxy, haloalkyl, haloalkoxy, aryl,        heteroaryl, or heterocyclyl is optionally substituted with 1-4        Z^(1c) groups;    -   each R⁶ is independently H, C₆-C₁₀ aryl or C₁-C₆ alkyl, wherein        said aryl or alkyl is optionally substituted with 1 to 4        substituents independently selected from halogen atoms, C₁-C₆        alkyl, C₆-C₁₀ aryl, C₃-C₈ carbocyclyl, 5-14 membered heteroaryl,        4-10 membered heterocyclyl, halo(C₁-C₆ alkoxy), —OH, —O(C₁-C₆        alkyl), —SH, —S(C₁-C₆ alkyl), —NH₂, —NH(C₁-C₆ alkyl), —N(C₁-C₆        alkyl)₂, —C(O)(C₁-C₆ alkyl), —SO₂N(C₁-C₆ alkyl)₂, —NHCOO(C₁-C₆        alkyl), —NHCO(C₁-C₆ alkyl), —NHCONH(C₁-C₆ alkyl), —CO₂(C₁-C₆        alkyl), or —C(O)N(C₁-C₆ alkyl)₂;    -   each W² is C₁-C₆ alkoxy substituted with a 5-14 membered        heteroaryl or C₆-C₁₀ aryl; wherein said heteroaryl or aryl is        substituted with 1-4 Z¹ groups;    -   each W³ is C₂-C₆ alkynyl group substituted with a C₆-C₁₀ aryl,        C₃-C₈ carbocyclyl, C₁-C₈ alkyl, C₁-C₆ haloalkyl, 4-10 membered        heterocyclyl, or 5-14 membered heteroaryl group; wherein said        aryl, carbocyclyl, alkyl, haloalkyl, heterocyclyl, or heteroaryl        group is optionally substituted with 1-4 Z¹ groups;    -   each W⁴ is —SF₅;    -   each W⁵ is —O(C₂-C₆ alkyl)OR²² wherein R²² is a C₆-C₁₀ aryl,        5-14 membered heteroaryl or 4-10 membered heterocyclyl group        optionally substituted with 1-4 Z¹ groups;    -   each W⁶ is —O(C₂-C₆ alkyl)NR¹⁶R²² wherein R²² is an aryl,        heteroaryl or heterocyclyl group optionally substituted with 1-4        Z¹ groups;    -   each W⁷ is —O(5-14 membered heteroaryl); wherein said —O(5-14        membered heteroaryl) is optionally substituted with 1-4 Z¹        groups and 2 adjacent substituents of said —O(5-14 membered        heteroaryl) may be taken together to form a 3- to 6-membered        cyclic ring containing 0 to 3 heteroatoms independently selected        from N, O, or S;    -   E is

-   -   E² is

-   -   E³ is

-   -   E⁴ is

-   -   Q¹ is H, C₁-C₈ alkyl, C₃-C₈ carbocyclyl, C₆-C₁₀ aryl, 5-6        membered heteroaryl, or 5-6 membered heterocyclyl groups,        wherein when Q¹ is not H, said Q¹ is optionally substituted with        1-4 substituents independently selected from halogen, —OR⁶,        —SR⁶, —N(R⁶)₂, C₆-C₁₀ aryl, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆        haloalkoxy, —CN, —CF₃, —SO₂(C₁-C₆ alkyl), —S(O)(C₁-C₆ alkyl),        —NR⁶SO₂Z², —SO₂NR¹⁷R¹⁸, —NHCOOR¹⁶, —NHCOZ², —NHCONHR¹⁶, —CO₂R⁶,        —C(O)R⁶ or —CON(R⁶)₂;    -   Q² is C₅-C₁₀ spiro bicyclic carbocyclyl optionally substituted        with 1-4 Z¹ groups;    -   Q³ is C₅-C₁₀ fused bicyclic carbocyclyl optionally substituted        with 1-4 Z¹ groups;    -   Q⁴ is C₅-C₁₀ bridged bicyclic carbocyclyl optionally substituted        with 1-4 Z¹ groups;    -   Q⁵ is 4-membered heterocyclyl having 1 heteroatom selected from        N, O or S wherein Q⁵ is optionally substituted with 1-4 Z³        groups;    -   Q⁷ is C₃-C₈ carbocyclyl substituted with 4-8 F atoms and each        carbon of Q⁷ is substituted with 0-2 F atoms;    -   each Z¹ is independently oxo, halogen, C₁-C₈ alkyl, C₂-C₈        alkenyl, C₂-C₈ alkynyl, C₃-C₈ carbocyclyl, C₅-C₁₀ bicyclic        carbocyclyl, C₁-C₈ haloalkyl, C₆-C₁₀ aryl, 5-14 membered        heteroaryl, 4-10 membered heterocyclyl, —CN, —C(O)R¹⁶,        —C(O)OR¹⁶, —C(O)NR¹⁷R¹⁸, —NR¹⁷R¹⁸, —NR¹⁶C(O)R¹⁶,        —NR¹⁶C(O)NR¹⁷R¹⁸, —NR¹⁶S(O)₂R¹⁶, —NR¹⁶S(O)₂NR¹⁷R¹⁸,        —NR¹⁶S(O)₂OR¹⁶, —OR¹⁶, —OC(O)R¹⁶, —OC(O)NR¹⁷R¹⁸, —SR¹⁶,        —S(O)R¹⁶, —S(O)₂R¹⁶ or —S(O)₂NR¹⁷R¹⁸ wherein any alkyl, alkenyl,        alkynyl, carbocyclyl, aryl, heteroaryl or heterocyclyl of Z¹ is        optionally substituted with 1-4 Z^(1a) groups;    -   each Z^(1a) is independently oxo, halogen, C₂-C₈ alkenyl, C₂-C₈        alkynyl, C₃-C₈ carbocyclyl, C₅-C₁₀ bicyclic carbocyclyl, C₁-C₈        haloalkyl, C₆-C₁₀ aryl, 5-14 membered heteroaryl, 4-10 membered        heterocyclyl, —CN, —C(O)R¹⁶, —C(O)OR¹⁶, —C(O)NR¹⁷R¹⁸, —NR¹⁷R¹⁸,        —NR¹⁶C(O)R¹⁶, —NR¹⁶C(O)OR¹⁶, —NR¹⁶C(O)NR¹⁷R¹⁸, —NR¹⁶S(O)₂R¹⁶,        —NR¹⁶S(O)₂NR¹⁷R¹⁸, —NR¹⁶S(O)₂OR¹⁶, —OR¹⁶, —OC(O)R¹⁶,        —OC(O)NR¹⁷R¹⁸, —SR¹⁶, —S(O)R¹⁶, —S(O)₂R¹⁶ or —S(O)₂NR¹⁷R¹⁸        wherein any alkenyl, alkynyl, carbocyclyl, aryl, heteroaryl or        heterocyclyl of Z^(1a) is optionally substituted with 1-4 Z^(1c)        groups;    -   each R¹⁶ is independently H, C₁-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈        alkynyl, C₃-C₈ carbocyclyl, C₅-C₁₀ bicyclic carbocyclyl, C₆-C₁₀        aryl, 5-14 membered heteroaryl or 4-10 membered heterocyclyl,        wherein any alkyl, alkenyl, alkynyl, carbocyclyl, aryl,        heteroaryl or heterocyclyl of R¹⁶ is optionally substituted with        1-4 Z^(1c) groups;    -   each Z^(1c) is independently oxo, halogen, C₁-C₈ alkyl, C₃-C₈        carbocyclyl, C₅-C₁₀ bicyclic carbocyclyl, C₁-C₈ haloalkyl,        C₆-C₁₀ aryl, 5-14 membered heteroaryl, 4-10 membered        heterocyclyl, —CN, —C(O)(C₁-C₈ alkyl), —C(O)O(C₁-C₈ alkyl),        —C(O)N(C₁-C₈ alkyl)₂, —NH₂, —NH(C₁-C₈ alkyl), —N(C₁-C₈ alkyl)₂,        —NHC(O)O(C₁-C₈ alkyl), —NHC(O)(C₁-C₈ alkyl), —NHC(O)NH(C₁-C₈        alkyl), —OH, —O(C₁-C₈ alkyl), C₃-C₈ cycloalkoxy, C₅-C₁₀ bicyclic        carbocyclyloxy, —S(C₁-C₈ alkyl) or —S(O)₂N(C₁-C₈ alkyl)₂ wherein        any alkyl, carbocyclyl, aryl, heteroaryl, heterocyclyl or        cycloalkoxy portion of Z^(1c) is optionally substituted with 1-4        halogen atoms or C₁-C₆ alkoxy groups;    -   R¹⁷ and R¹⁸ are each independently H, C₁-C₈ alkyl, C₂-C₈        alkenyl, C₂-C₈ alkynyl, C₃-C₈ carbocyclyl, C₅-C₁₀ bicyclic        carbocyclyl, —C(O)R¹⁶, —C(O)OR¹⁶, C₆-C₁₀ aryl, 5-14 membered        heteroaryl or 4-10 membered heterocyclyl, wherein any alkyl,        alkenyl, alkynyl, carbocyclyl, aryl, heteroaryl or heterocyclyl        of R¹⁷ or R¹⁸ is optionally substituted with 1-4 Z^(1c) groups,        or R¹⁷ and R¹⁸ together with the nitrogen to which they are        attached form a 4-7 membered heterocyclyl group, wherein said        4-7 membered heterocyclyl group is optionally substituted with        1-4 Z^(1c) groups;    -   each Z² is independently C₁-C₈ alkyl, C₃-C₈ carbocyclyl, C₅-C₁₀        bicyclic carbocyclyl, C₆-C₁₀ aryl, 5-14 membered heteroaryl,        4-10 membered heterocyclyl, —NR¹⁷R¹⁸ or —OR¹⁶ wherein any alkyl,        carbocyclyl, aryl, heteroaryl or heterocyclyl portion of Z² is        optionally substituted with 1-4 Z^(2a) groups;    -   each Z^(2a) is independently oxo, halogen, C₁-C₈ alkyl, C₂-C₈        alkynyl, C₃-C₈ carbocyclyl, C₅-C₁₀ bicyclic carbocyclyl, C₁-C₈        haloalkyl, C₆-C₁₀ aryl, 5-14 membered heteroaryl, 4-10 membered        heterocyclyl, —(C₂-C₈ alkynyl)aryl, —(C₂-C₈ alkynyl)heteroaryl,        —CN, —C(O)(C₁-C₆ alkyl), —C(O)O(C₁-C₆ alkyl), —C(O)N(C₁-C₆        alkyl)₂, —NH₂, —NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)₂,        —NHC(O)O(C₁-C₆ alkyl), —NHC(O)(C₁-C₆ alkyl), —NHC(O)NH(C₁-C₆        alkyl), —OH, —O(C₁-C₆ alkyl), halo(C₁-C₆ alkoxy), C₃-C₈        cycloalkoxy, —S(C₁-C₆ alkyl), or —SO₂N(C₁-C₆ alkyl)₂; wherein        any alkyl, alkynyl, carbocyclyl, cycloalkoxy, aryl, heteroaryl        or heterocyclyl portions of Z^(2a) is optionally substituted        with 1-4 halogen or C₁-C₆ alkoxy groups;    -   each Z³ is independently oxo, halogen, C₂-C₈ alkenyl, C₂-C₈        alkynyl, C₃-C₈ carbocyclyl, C₅-C₁₀ bicyclic carbocyclyl, C₁-C₈        haloalkyl, C₆-C₁₀ aryl, 5-14 membered heteroaryl, 4-10 membered        heterocyclyl, —CN, —C(O)OR¹⁶, —C(O)NR¹⁷R¹⁸, —NR¹⁷R¹⁸,        —NR¹⁶C(O)NR¹⁷R¹⁸, —OR¹⁶, —SR¹⁶ or —SO₂R¹⁶; wherein any alkenyl,        alkynyl, carbocyclyl, aryl, heteroaryl or heterocyclyl portions        of Z³ is optionally substituted with 1-4 halogen; and    -   each Z⁴ is independently oxo, C₂-C₈ alkenyl, C₂-C₈ alkynyl,        C₃-C₈ carbocyclyl, C₅-C₁₀ bicyclic carbocyclyl, C₁-C₈ haloalkyl,        C₆-C₁₀ aryl, 5-14 membered heteroaryl, 4-10 membered        heterocyclyl, —CN, —C(O)OR¹⁶, —C(O)NR¹⁷R¹⁸, —NR¹⁷R¹⁸,        —NR¹⁶C(O)NR¹⁷R¹⁸, —OR¹⁶, —SR¹⁶ or —SO₂R¹⁶, wherein any alkenyl,        alkynyl, carbocyclyl, aryl, heteroaryl or heterocyclyl portions        of Z⁴ is optionally substituted with 1-4 halogen.

One embodiment provides a pharmaceutical composition comprising acompound of Formula I, II, III, or IV (such as any one of IVa-IVh), or astereoisomer, or a mixture of stereoisomers, or a pharmaceuticallyacceptable salt thereof, and a pharmaceutically acceptable carrier.

One embodiment provides a method for treating a Flaviviridae viralinfection (e.g., an HCV viral infection) in a patient in need thereof(e.g., mammal such as a human). The method includes administering acompound of Formula I, II, III, or IV (such as any one of IVa-IVh), or astereoisomer, or a mixture of stereoisomers, or a pharmaceuticallyacceptable salt thereof, to the patient.

One embodiment provides a method for inhibiting the proliferation of theHCV virus, treating HCV or delaying the onset of HCV symptoms in apatient in need thereof (e.g., mammal such as a human). The methodincludes administering a compound of Formula I, II, III, or IV (such asany one of IVa-IVh) or a stereoisomer, or a mixture of stereoisomers, ora pharmaceutically acceptable salt thereof, to the patient.

One embodiment provides a compound of Formula I, II, III, or IV (such asany one of IVa-IVh) or a stereoisomer, or a mixture of stereoisomers, ora pharmaceutically acceptable salt thereof for use in medical therapy(e.g., for use in treating a Flaviviridae viral infection such as an HCVviral infection or in treating the proliferation of the HCV virus ordelaying the onset of HCV symptoms in a patient in need thereof (e.g.,mammal such as a human)).

One embodiment provides a compound of Formula I, II, III, or IV (such asany one of IVa-IVh), or a stereoisomer, or a mixture of stereoisomers,or a pharmaceutically acceptable salt thereof for use in the manufactureof a medicament for treating a Flaviviridae viral infection (e.g., anHCV viral infection) or the proliferation of the HCV virus or delayingthe onset of HCV symptoms in a patient in need thereof (e.g., mammalsuch as a human).

One embodiment provides a compound of Formula I, II, III, or IV (such asany one of IVa-IVh), or a stereoisomer, or a mixture of stereoisomers,or a pharmaceutically acceptable salt thereof, for use in theprophylactic or therapeutic treatment of the proliferation of aFlaviviridae virus, an HCV virus or for use in the therapeutic treatmentof delaying the onset of HCV symptoms.

One embodiment provides a compound of Formula I, II, III, or IV (such asany one of IVa-IVh) or a stereoisomer, or a mixture of stereoisomers, ora pharmaceutically acceptable salt thereof, for use in the prophylacticor therapeutic treatment of a Flaviviridae virus infection (e.g., an HCVvirus infection).

One embodiment provides the use of a compound of Formula I, II, III, orIV (such as any one of IVa-IVh), or a stereoisomer, or a mixture ofstereoisomers, or a pharmaceutically acceptable salt thereof, for themanufacture of a medicament for a Flaviviridae virus infection (e.g., anHCV virus infection) in a patient in need thereof (e.g., mammal such asa human).

One embodiment provides processes and intermediates disclosed hereinthat are useful for preparing compounds of Formula I, II, III, or IV(such as any one of IVa-IVh) or a stereoisomer, or a mixture ofstereoisomers, or salts thereof.

Other embodiments, objects, features and advantages will be set forth inthe detailed description of the embodiments that follows, and in partwill be apparent from the description, or may be learned by practice, ofthe claimed invention. These objects and advantages will be realized andattained by the processes and compositions particularly pointed out inthe written description and claims hereof. The foregoing Summary hasbeen made with the understanding that it is to be considered as a briefand general synopsis of some of the embodiments disclosed herein, isprovided solely for the benefit and convenience of the reader, and isnot intended to limit in any manner the scope, or range of equivalents,to which the appended claims are lawfully entitled.

DETAILED DESCRIPTION

While the present invention is capable of being embodied in variousforms, the description below of several embodiments is made with theunderstanding that the present disclosure is to be considered as anexemplification of the claimed subject matter, and is not intended tolimit the appended claims to the specific embodiments illustrated. Theheadings used throughout this disclosure are provided for convenienceonly and are not to be construed to limit the claims in any way.Embodiments illustrated under any heading may be combined withembodiments illustrated under any other heading.

ABBREVIATIONS

The following abbreviations are used throughout the specification, andhave the following meanings:

-   ° C.=degrees Celsius-   A=Angstrom-   Ac=acetyl-   AcOH=acetic acid-   aq=aqueous-   Ar=argon-   atm=atmosphere-   BEP=2-bromo-1-ethyl pyridinium tetrafluoroborate-   Bis(diphenylphosphino)ferrocene)palladium(II) dichloride-   Bn=benzyl-   Boc=tert-butoxy carbonyl-   Boc₂O=di-tert-butyl dicarbonate-   bp=boiling point-   Bs=4-bromophenylsulfonyl-   Bu=butyl-   calcd=calculated-   CBS=Corey-Bakshi-Shibata-   CBZ=Cbz=carboxybenzyl-   CDI=1,1′-carbonyldiimidazole-   cm=centermeter-   COMU=(1-cyano-2-ethoxy-2-oxoethylidenam inooxy)dimethylam    ino-morpholino-carbenium hexafluorophosphate-   DABCO=1,4-diazabicyclo[2.2.2]octane-   DBU=1,8-diazabicycloundec-7-ene-   DCE=1,2-dichloroethane-   DCM=dichloromethane-   DIAD=diisopropyl azodicarboxylate-   dioxane=1,4-dioxane-   DIPEA=N,N-diisopropyl-N-ethylamine-   DMF=N,N-dimethylformamide-   DMAP=4-dimethylaminopyridine-   DMPU=1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone-   DMSO=dimethysulfoxide-   dppf=1,1′-bis(diphenylphosphino)ferrocene-   DSC=N,N′-disuccinimidyl carbonate-   EA=EtOAc=ethyl acetate-   EC₅₀=half maximal effective concentration-   EDC=1-ethyl-3-(3-dimethylaminopropyl)carbodiimide-   Et=ethyl-   Et₂O=diethyl ether-   EtOAc=ethyl acetate-   EtOH=ethanol-   equiv=equivalent-   F-NMR=fluorine nuclear magnetic resonance spectroscopy-   g=gram-   h=hour-   HATU=O-(7-azabenzotriazol-1-yl)-N,N,N,N′-tetramethyluronium    Hexafluorophosphate-   HCV=hepatitis C virus-   Hex=hex=hexanes-   HMDS=hexamethyldisilazane(azide)-   HMPA=hexamethylphosphoramide-   ¹H-NMR=proton nuclear magnetic resonance spectroscopy-   HOAc=acetic acid-   HOBT=hydroxybenzotriazole-   HPLC=high pressure liquid chromatography-   Hz=Hertz-   IPA=isopropyl alcohol-   i=iso-   J=coupling constant-   KHMDS=potassium bis(trimethylsilyl)amide-   L=liter-   LCMS-ESI=liquid chromatography mass spectrometer (electrospray    ionization)-   LiHMDS=lithium bis(trimethylsilyl)amide-   M=molar concentration (mol/L)-   Me=methyl-   MeCN=acetonitrile-   MeOH=methanol-   MeTHF=2-methyltetrahydrofuran-   mg=milligram-   MHz=mega Hertz-   mL=milliliter-   mmol=millimole-   min=minute-   MTBE=methyl tert-butylether-   Ms=methanesulfonyl-   MsCl=methanesulfonyl chloride-   MS=molecular sieves-   MSA=methylsulfonic acid-   n=normal-   N=normal concentration-   NCS=N-chlorosuccinimide-   NMM=N-methylmorpholine-   NMO=N-methylmorpholine-N-oxide-   NMP=N-methylpyrrolidinone-   o/n=overnight-   Pf=9-phenyl-9H-fluoren-9-yl-   PG=protecting group-   PE=petroleum ether-   Ph=phenyl-   PhMe=toluene-   pM=picomolar-   PMB=4-methoxybenzyl-   Pr=propyl-   Pd(dppf)Cl₂═PdCl₂(dppf)=PdCl₂dppf=(1,1′-bis(diphenylphosphino)ferrocene)dichloropalladium(II)-   PPh₃=triphenylphosphine-   rt=room temperature-   sat=sat.=saturated-   sec=secondary-   S_(N)1=nucleophilic substitution unimolecular-   S_(N)2=nucleophilic substitution bimolecular-   S_(N)Ar=nucleophilic substitution aromatic-   t=tert=tertiary-   TBAF=tetra-n-butylammonium fluoride-   TBS=TBDMS=tert-Butyldimethylsilyl-   TBTU=O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium    tetrafluoroborate-   TEA=triethylamine-   temp=temperature-   TEMPO=(2,2,6,6-Tetramethylpiperidin-1-yl)oxyl-   Tf=trifluoromethanesulfonyl-   TFA=trifluoroacetic acid-   THF=tetrahydrofuran-   TIPS=triisoproylsilyl-   TLC=thin layer chromatography-   TMS=trimethylsilyl-   TMSOTf=trimethylsilyl trifluoromethanesulfonate-   TPAP=tetrapropylammonium perruthenate-   Tr=triphenylmethyl-   Ts=para-toluenesulfonyl-   w/w=weight/weight ratio

DEFINITIONS

Unless stated otherwise, the following terms and phrases as used hereinare intended to have the following meanings:

When a cyclic group (e.g. cycloalkyl, carbocyclyl, bicyclic carbocyclyl,heteroaryl, heterocyclyl) is limited by a number or range of numbers,the number or numbers refer to the number of atoms making up the cyclicgroup, including any heteroatoms. Therefore, for example, a 4-8 memberedheterocyclyl group has 4, 5, 6, 7 or 8 ring atoms.

“Alkenyl” refers to a straight or branched chain hydrocarbyl with atleast one site of unsaturation, e.g., a (sp²)carbon-(sp²)carbon doublebond. For example, an alkenyl group can have 2 to 8 carbon atoms (i.e.,C₂-C₈ alkenyl), or 2 to 6 carbon atoms (i.e., C₂-C₆ alkenyl). Examplesof suitable alkenyl groups include, but are not limited to, ethylene orvinyl (—CH═CH₂) and allyl (—CH₂CH═CH₂).

“Alkenylene” refers to an alkene having two monovalent radical centersderived by the removal of two hydrogen atoms from the same or twodifferent carbon atoms of a parent alkene. Exemplary alkenylene radicalsinclude, but are not limited to, 1,2-ethenylene (—CH═CH—) orprop-1-enylene (—CH₂CH═CH—).

“Alkoxy” is RO— where R is alkyl, as defined herein. Non-limitingexamples of alkoxy groups include methoxy, ethoxy and propoxy.

“Alkyl” refers to a saturated, straight or branched chain hydrocarbylradical. For example, an alkyl group can have 1 to 8 carbon atoms (i.e.,(C₁-C₈)alkyl) or 1 to 6 carbon atoms (i.e., (C₁-C₆ alkyl) or 1 to 4carbon atoms. Examples of alkyl groups include, but are not limited to,methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl,hexyl, heptyl, octyl, nonyl and decyl.

“Alkylene” refers to an alkyl having two monovalent radical centersderived by the removal of two hydrogen atoms from the same or twodifferent carbon atoms of a parent alkane. Examples of alkylene radicalsinclude, but are not limited to, methylene (—CH₂—), ethylene (—CH₂CH₂—),propylene (—CH₂CH₂CH₂—) and butylene (—CH₂CH₂CH₂CH₂—).

“Alkynyl” refers to a straight or branched chain hydrocarbon with atleast one site of unsaturation, e.g., a (sp)carbon-(sp)carbon triplebond. For example, an alkynyl group can have 2 to 8 carbon atoms (C₂-C₈alkyne) or 2 to 6 carbon atoms (C₂-C₆ alkynyl). Examples of alkynylgroups include, but are not limited to, acetylenyl (—C≡CH) and propargyl(—CH₂C≡CH) groups.

“Alkynylene” refers to an alkynyl having two monovalent radical centersderived by the removal of two hydrogen atoms from the same or twodifferent carbon atoms of a parent alkyne. Typical alkynylene radicalsinclude, but are not limited to, acetylene (—C≡C—), propargylene(—CH₂C≡C—), and 1-pentynylene (—CH₂CH₂CH₂C≡C—).

“Aryl” refers to a single all carbon aromatic ring or a multiplecondensed all carbon ring system (e.g., a fused multicyclic ring system)wherein at least one of the rings is aromatic. For example, an arylgroup can have 6 to 20 carbon atoms, 6 to 14 carbon atoms, or 6 to 12carbon atoms. It is to be understood that the point of attachment of amultiple condensed ring system, as defined above, can be at any positionof the ring system including an aromatic or a carbocyclyl portion of thering. Examples of aryl groups include, but are not limited to, phenyl,naphthyl, tetrahydronaphthyl and indanyl.

“Arylene” refers to an aryl as defined herein having two monovalentradical centers derived by the removal of two hydrogen atoms from twodifferent carbon atoms of a parent aryl. Typical arylene radicalsinclude, but are not limited to, phenylene, e.g.,

and naphthylene, e.g.,

“Bicyclic carbocyclyl” refers to a 5-14 membered saturated or partiallyunsaturated bicyclic fused, bridged, or spiro ring hydrocarbon attachedvia a ring carbon. In a spiro bicyclic carbocyclyl, the two rings sharea single common carbon atom. In a fused bicyclic carbocyclyl, the tworings share two common and adjacent carbon atoms. In a bridged bicycliccarbocyclyl, the two rings share three or more common, non-adjacentcarbon atoms. Examples of bicyclic carbocyclyl groups include, but arenot limited to spiro bicyclic carbocyclyl groups wherein two carbocyclylrings share one common atom

fused bicyclic carbocyclyl groups wherein two carbocyclyl rings sharetwo common atoms

and bridged bicyclic carbocyclyl groups wherein two carbocyclyl ringsshare three or more (such as 3, 4, 5 or 6) common atoms

“Bicyclic carbocyclylene” refers to a bicyclic carbocyclyl, as definedabove, having two monovalent radical centers derived from the removal oftwo hydrogen atoms from the same or two different carbon atom of aparent bicyclic carbocyclyl. Examples of bicyclic carbocyclylene groupsinclude, but are not limited to, spiro bicyclic carbocyclylene groupswherein two carbocyclyl rings share one common atom

fused bicyclic carbocyclylene groups wherein two carbocyclyl rings sharetwo common atoms

and bridged bicyclic carbocyclylene groups wherein two carbocyclyl ringsshare three or more (such as 3, 4, 5 or 6) common atoms

“Carbocyclyloxy” is RO— where R is carbocyclyl, as defined herein.

“Bicyclic carbocyclyloxy” is RO— where R is bicyclic carbocyclyl, asdefined herein.

“Carbocyclyl”, and “carbocycle” refers to a hydrocarbyl group containingone saturated or partially unsaturated ring structure, attached via aring carbon. In various embodiments, carbocyclyl refers to a saturatedor a partially unsaturated C₃-C₁₂ cyclic moiety, examples of whichinclude cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl,cyclohexenyl, cycloheptyl and cyclooctyl.

“Carbocyclylene” (as well as “carbocyclene”) refers to a carbocyclyl, asdefined herein, having two monovalent radical centers derived by theremoval of two hydrogen atoms from the same or two different carbonatoms of a parent carbocyclyl. Examples of carbocyclene include, but arenot limited to, cyclopropylene, cyclobutylene, cyclopentylene andcyclohexylene.

“Carbocyclylalkyl” refers to a hydrocarbyl group containing onesaturated or partially unsaturated ring structure attached to an alkylgroup, attached via a ring carbon or an alkyl carbon. In variousembodiments, carbocyclylalkyl refers to a saturated or a partiallyunsaturated C₁-C₁₂ carbocyclylalkyl moiety, examples of which includecyclopropylalkyl, cyclobutylalkyl, cyclopropylethyl, andcyclopropylpropyl.

“Carbocyclylalkylene” refers to a carbocyclylalkyl, as defined herein,having two monovalent radical centers derived by the removal of twohydrogen atoms from the same or two different carbon atoms of a parentcycloalkylalkyl. Examples of cycloalkylene include, but are not limitedto, cyclopropylmethylene and cyclopropylmethylene.

“Cycloalkyl” refers to a hydrocarbyl group containing one saturated ringstructure, attached via a ring carbon. In various embodiments,cycloalkyl refers to a saturated C₃-C₁₂ cyclic moiety, examples of whichinclude cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyland cyclooctyl.

“Cycloalkoxy” is RO— where R is cycloalkyl, as defined herein.

“Direct bond” refers a covalent bond between two atoms.

“Halo” or “halogen” refers to chloro (—Cl), bromo (—Br), fluoro (—F) oriodo (—I).

“Haloalkenyl” refers to alkenyl group, as defined herein, substitutedwith one or more halogen atoms.

“Haloalkoxy” refers to alkoxy, as defined herein, substituted with oneor more halogen atoms.

“Haloalkyl” refers to an alkyl group, in which one or more hydrogenatoms of the alkyl group is replaced with a halogen atom. Examples ofhaloalkyl groups include, but are not limited to, —CF₃, —CHF₂, —CFH₂ and—CH₂CF₃.

“Haloalkylene” refers to alkylene group, as defined herein, substitutedwith one or more halogen atoms.

“Heteroalkyl” refers to an alkyl group, as defined herein, in which oneor more carbon atoms is replaced with an oxygen, sulfur, or nitrogenatom.

“Heteroalkylene” refers to an alkylene group, as defined herein, inwhich one or more carbon atoms is replaced with an oxygen, sulfur, ornitrogen atom.

“Heteroalkenyl” refers to an alkenyl group, as defined herein, in whichone or more carbon atoms is replaced with an oxygen, sulfur, or nitrogenatom.

“Heteroalkenylene” refers to heteroalkenyl group, as defined above,having two monovalent radical centers derived by the removal of twohydrogen atoms from the same or two different atoms of a parentheteroalkenyl group.

“Heteroaryl” refers to a single aromatic ring that has at least one atomother than carbon in the ring, wherein the atom is selected from thegroup consisting of oxygen, nitrogen and sulfur; the term also includesmultiple condensed ring systems that have at least one such aromaticring. For example, heteroaryl includes monocyclic, bicyclic or tricyclicring having up to 6 atoms in each ring, wherein at least one ring isaromatic and contains from 1 to 4 heteroatoms in the ring selected fromthe group consisting of oxygen, nitrogen and sulfur. The rings of themultiple condensed ring system can be connected to each other via fused,spiro and bridged bonds when allowed by valency requirements.Non-limiting examples of heteroaryl include pyridyl, thienyl, furanyl,pyrimidyl, imidazolyl, pyranyl, pyrazolyl, thiazolyl, thiadiazolyl,isothiazolyl, oxazolyl, isoxazolyl, pyrrolyl, pyridazinyl, pyrazinyl,quinolinyl, isoquinolinyl, quinoxalinyl, benzofuranyl, dibenzofuranyl,dibenzothiophenyl, benzothienyl, indolyl, benzothiazolyl, benzooxazolyl,benzimidazolyl, isoindolyl, benzotriazolyl, purinyl, thianaphthenyl andpyrazinyl. Attachment of heteroaryl can occur via an aromatic ring, or,if heteroaryl is bicyclic or tricyclic and one of the rings is notaromatic or contains no heteroatoms, through a non-aromatic ring or aring containing no heteroatoms. “Heteroaryl” is also understood toinclude the N-oxide derivative of any nitrogen containing heteroaryl.

“Heteroarylene” refers to a heteroaryl, as defined above, having twomonovalent radical centers derived by the removal of two hydrogen atomsfrom the same or two different carbon atoms or the removal of a hydrogenfrom one carbon atom and the removal of a hydrogen atom from onenitrogen atom of a parent heteroaryl group. Non-limiting examples ofheteroarylene groups are:

“Heterocyclyl” refers to a saturated or partially unsaturatedmonocyclic, bicyclic or tricyclic group of 2 to 14 ring-carbon atomsand, in addition to ring-carbon atoms, 1 to 4 heteroatoms selected fromnitrogen, oxygen and sulfer. Bi- or tricyclic heterocyclyl groups mayhave fused, bridged, or spiro ring connectivity. In various embodimentsthe heterocyclic group is attached to another moiety through carbon orthrough a heteroatom. Examples of heterocyclyl include withoutlimitation azetidinyl, oxazolinyl, isoxazolinyl, oxetanyl,tetrahydropyranyl, tetrahydrothiopyranyl, tetrahydroisoquinolinyl,1,4-dioxanyl, pyrrolidinyl, morpholinyl, thiomorpholinyl,dihydrobenzoimidazolyl, dihydrobenzofuranyl, dihydrobenzothiophenyl,dihydrobenzoxazolyl, dihydrofuranyl, dihydroimidazolyl, dihydroindolyl,dihydroisooxazolyl, dihydroisothiazolyl, dihydrooxadiazolyl,dihydrooxazolyl, dihydropyrazinyl, dihydropyrazolyl, dihydropyridinyl,dihydropyrimidinyl, dihydropyrrolyl, dihydroquinolinyl,dihydrotetrazolyl, dihydrothiadiazolyl, dihydrothiazolyl,dihydrothienyl, dihydrotriazolyl, dihydroazetidinyl,methylenedioxybenzoyl, chromanyl, dihydropyranoquinoxalinyl,tetrahydroquinoxalinyl, tetrahydroquinolinyl, dihydropyranoquinolinyland tetrahydrothienyl and N-oxides thereof. A spiro bicyclicheterocyclyl group refers to a bicyclic heterocyclyl group wherein thetwo rings of the bicyclic heterocyclyl group share one common atom. Afused bicyclic bicyclic heterocyclyl group refers to a bicyclicheterocyclyl group wherein the two rings of the bicyclic heterocyclylgroup share two common atoms. A bridged bicyclic heterocyclyl grouprefers to a bicyclic heterocyclyl group wherein the two rings of thebicyclic heterocyclyl group share three or more (such as 3, 4, 5 or 6)common atoms.

“Heterocyclene” refers to a heterocyclyl, as defined herein, having twomonovalent radical centers derived from the removal of two hydrogenatoms from the same or two different carbon atoms, through a carbon anda heteroatom, or through two heteroatoms of a parent heterocycle.

“Prodrug” refers to any compound that when administered to a biologicalsystem generates the drug substance, or active ingredient, as a resultof spontaneous chemical reaction(s), enzyme catalyzed chemicalreaction(s), photolysis, and/or metabolic chemical reaction(s). Aprodrug is thus a covalently modified analog or latent form of atherapeutically active compound. Non-limiting examples of prodrugsinclude ester moieties, quaternary ammonium moieties, glycol moieties,and the like.

The term “optionally substituted” refers to a moiety wherein allsubstituents are hydrogen or wherein one or more of the hydrogens of themoiety are replaced by non-hydrogen substituents; that is to say themoiety that is optionally substituted is either substituted orunsubstituted.

“Leaving group” (LG) refers to a moiety of a compound that is activetowards displacement or substitution in a chemical reaction. Examples ofin which such as displacement or substitution occur include, but are notlimited to, nucleophilic substitution bimolecular (S_(N)2), nucleophilicsubstitution unimolecular (S_(N)1), nucleophilic aromatic substitution(S_(N)Ar), and transition metal catalyzed cross-couplings. Examples ofleaving groups include, but are not limited to, a halogen atom (e.g.—Cl, —Br, —I) and sulfonates (e.g. mesylate (—OMs), tosylate (—OTs) ortriflate (—OTf)). The skilled artisan will be aware of various chemicalleaving groups and strategies for activation and will appreciate theappropriate moiety that will act as leaving groups, based on theparticular chemical reaction, the functionality that the group isattached to, and the chemical reagents used to affect the displacementor substitution reaction. As a non-limiting example, in some situations,a halogen atom (e.g. —Cl, —Br, or —I) serves as a leaving group in areaction catalyzed by a transition metal (e.g. Pd catalyzed Suzukicoupling between an aryl halide and aryl boronic acid) and anotherreagents such as a base.

Stereoisomers

Stereochemical definitions and conventions used herein generally followS. P. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984)McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S.,Stereochemistry of Organic Compounds (1994) John Wiley & Sons, Inc., NewYork.

The term “chiral” refers to molecules which have the property ofnon-superimposability of the mirror image partner, while the term“achiral” refers to molecules which are superimposable on their mirrorimage partner.

“Isomers” are different compounds that have the same molecular formula.Isomers include stereoisomers, enantiomers and diastereomers.

“Diastereoisomers” are stereoisomers that have at least two asymmetricatoms, but which are not mirror-images of each other.

“Enantiomers” are a pair of stereoisomers that are non-superimposablemirror images of each other. A 1:1 mixture of a pair of enantiomers is a“racemic” mixture. The term “(±)” is used to designate a racemic mixturewhere appropriate.

The term “stereoisomers” refers to compounds which have identicalchemical constitution, but differ with regard to the arrangement of theatoms or groups in space.

The compounds disclosed herein may have chiral centers, e.g., chiralcarbon atoms. Such compounds thus include racemic mixtures of allstereoisomers, including enantiomers, diastereomers, and atropisomers.In addition, the compounds disclosed herein include enriched or resolvedoptical isomers at any or all asymmetric, chiral atoms. In other words,the chiral centers apparent from the depictions are provided as thechiral isomers or racemic mixtures. Both racemic and diastereomericmixtures, as well as the individual optical isomers isolated orsynthesized, substantially free of their enantiomeric or diastereomericpartners, are all within the scope of the invention. The racemicmixtures can be separated into their individual, substantially opticallypure isomers through well-known techniques such as, for example, theseparation of diastereomeric salts formed with optically activeadjuncts, e.g., acids or bases followed by conversion back to theoptically active substances. The desired optical isomer can also besynthesized by means of stereospecific reactions, beginning with theappropriate stereoisomer of the desired starting material.

It is to be understood that for compounds disclosed herein when a bondis drawn in a non-stereochemical manner (e.g., flat) the atom to whichthe bond is attached includes all stereochemical possibilities. It isalso to be understood that when a bond is drawn in a stereochemicalmanner (e.g., bold, bold-wedge, dashed or dashed-wedge) the atom towhich the stereochemical bond is attached has the stereochemistry asshown unless otherwise noted. Accordingly, in one embodiment, a compounddisclosed herein is greater than 50% a single enantiomer. In anotherembodiment, a compound disclosed herein is at least 80% a singleenantiomer. In another embodiment, a compound disclosed herein is atleast 90% a single enantiomer. In another embodiment, a compounddisclosed herein is at least 98% a single enantiomer. In anotherembodiment, a compound disclosed herein is at least 99% a singleenantiomer. In another embodiment, a compound disclosed herein isgreater than 50% a single diastereomer. In another embodiment, acompound disclosed herein is at least 80% a single diastereomer. Inanother embodiment, a compound disclosed herein is at least 90% a singlediastereomer. In another embodiment, a compound disclosed herein is atleast 98% a single diastereomer. In another embodiment, a compounddisclosed herein is at least 99% a single diastereomer.

Tautomers

The compounds disclosed herein can also exist as tautomeric isomers incertain cases. Although only one delocalized resonance structure may bedepicted, all such forms are contemplated within the scope of theinvention. For example, ene-amine tautomers can exist for purine,pyrimidine, imidazole, guanidine, amidine, and tetrazole systems and alltheir possible tautomeric forms are within the scope of the invention.

Isotopes

It is understood by one skilled in the art that this invention alsoincludes any compound claimed that may be enriched at any or all atomsabove naturally occurring isotopic ratios with one or more isotopes suchas, but not limited to, deuterium (²H or D). As a non-limiting example,a —CH₃ group may be replaced by —CD₃.

Specific values listed below for radicals, substituents, and ranges arefor illustration only; they do not exclude other defined values or othervalues within defined ranges for the radicals and substituents.

Protecting Groups

In certain embodiments, protecting groups include prodrug moieties andchemical protecting groups. Protecting groups may be represented by theabbreviation “PG.”

“Protecting group” (“PG”) refers to a moiety of a compound that masks oralters the properties of a functional group or the properties of thecompound as a whole. Chemical protecting groups and strategies forprotection/deprotection are well known in the art. See e.g. Peter G. M.Wuts and Theodora W. Greene, Protective Groups in Organic Synthesis,4^(th) edition; John Wiley & Sons, Inc.: New Jersey, 2007. See alsoKocienski, P. J. Protecting Groups, 3^(rd) edition; Georg Thieme VerlagStuttgart: New York, 2005, in particular Chapter 1, Protecting Groups:An Overview, pages 1-48, Chapter 2, Carbonyl Protecting Groups, pages49-118, Chapter 3, Diol Protecting Groups, pages 119-186, Chapter 4,Hydroxyl Protecting Groups, pages 187-364, Chapter 5, Thiol ProtectingGroups, pages 365-392. Protecting groups are often utilized to mask thereactivity of certain functional groups, to assist in the efficiency ofdesired chemical reactions, e.g., making and breaking chemical bonds inan ordered and planned fashion.

Protection of functional groups of a compound alters other physicalproperties besides the reactivity of the protected functional group,such as the polarity, lipophilicity (hydrophobicity), and otherproperties which can be measured by common analytical tools. Chemicallyprotected intermediates may themselves be biologically active orinactive.

In certain embodiments, protecting groups are optionally employed toprevent side reactions with the protected group during syntheticprocedures. Selection of the appropriate groups to protect, when to doso, and the nature of the chemical protecting group “PG” is dependentupon the chemistry of the reaction to be protected against (e.g.,acidic, basic, oxidative, reductive or other conditions) and theintended direction of the synthesis. PGs do not need to be, andgenerally are not, the same if the compound is substituted with multiplePG. In general, PG will be used to protect functional groups such ascarboxyl, hydroxyl, thio, or amino groups and to thus prevent sidereactions or to otherwise facilitate the synthetic efficiency. The orderof deprotection to yield free deprotected groups is dependent upon theintended direction of the synthesis and the reaction conditions to beencountered, and may occur in any order as determined by the artisan.

Salts and Hydrates

Examples of pharmaceutically acceptable salts of the compounds disclosedherein include salts derived from an appropriate base, such as an alkalimetal (for example, sodium), an alkaline earth metal (for example,magnesium), ammonium and NX₄ (wherein X is C₁-C₄ alkyl).Pharmaceutically acceptable salts of a nitrogen atom or an amino groupinclude for example salts of organic carboxylic acids such as acetic,benzoic, lactic, fumaric, tartaric, maleic, malonic, malic, isethionic,lactobionic and succinic acids; organic sulfonic acids, such asmethanesulfonic, ethanesulfonic, benzenesulfonic and p-toluenesulfonicacids; and inorganic acids, such as hydrochloric, hydrobromic, sulfuric,phosphoric and sulfamic acids. Pharmaceutically acceptable salts of acompound of a hydroxy group include the anion of said compound incombination with a suitable cation such as Na⁺ and NX₄ ⁺ (wherein each Xis independently selected from H or a C₁-C₄ alkyl group).

For therapeutic use, salts of active ingredients of the compoundsdisclosed herein will typically be pharmaceutically acceptable, i.e.,they will be salts derived from a physiologically acceptable acid orbase. However, salts of acids or bases which are not pharmaceuticallyacceptable may also find use, for example, in the preparation orpurification of a compound of Formula I, II, III or IV, (such as any oneof IVa-IVh) or a stereoisomer, or a mixture of stereoisomers, or anothercompound disclosed herein. All salts, whether or not derived from aphysiologically acceptable acid or base, are within the scope of thepresent invention.

Metal salts typically are prepared by reacting the metal hydroxide witha compound disclosed herein. Examples of metal salts which are preparedin this way are salts containing Li⁺, Na⁺, and K⁺. A less soluble metalsalt can be precipitated from the solution of a more soluble salt byaddition of the suitable metal compound.

In addition, salts may be formed from acid addition of certain organicand inorganic acids, e.g., HCl, HBr, H₂SO₄, H₃PO₄ or organic sulfonicacids, to basic centers, such as amines. Finally, it is to be understoodthat the compositions herein comprise compounds disclosed herein intheir un-ionized, as well as zwitterionic form, and combinations withstoichiometric amounts of water as in hydrates.

EMBODIMENTS

In certain embodiments, A is —C(O)—, 6-10 membered arylene, or 5-6membered heteroarylene group, wherein said arylene or heteroarylene isoptionally substituted with 1-4 halogens or haloalkyl groups. In someembodiments, A is —C(O)—.

In certain embodiments, M is —O— or a bond. In some embodiments, M is—O—.

In certain embodiments, G is —CO₂H or —CONHSO₂Z². In some embodiments, Gis —CONHSO₂Z². In some embodiments, G is —CONHSO₂Z² and Z² iscyclopropyl optionally substituted with methyl.

In certain embodiments, G is:

In some embodiments, G is:

In certain embodiments, Z² is:

In certain embodiments, Z² is:

In certain embodiments, Z^(2a) is hydrogen, halogen or methyl. In someembodiments, Z^(2a) is:

In other embodiments, Z^(2a) is

(i.e., hydrogen or methyl).

In other embodiments, Z^(2a) is

In still more embodiments, Z^(2a) is (i.e., methyl).

In certain embodiments, one of R³, R⁴, and R⁵ is Z¹ and the other twoare H. In some embodiments, R³, R⁴ and R⁵ are each H.

In certain embodiments, X is —OC(O)—, —O—, or a direct bond. In someembodiments, X is —O—.

In certain embodiments, X is —OC(O)—, —O—, or a direct bond. In certainother embodiments, X is —O—.

In certain embodiments, {circle around (T)} is C₃-C₆ carbocyclylene thatis attached to L and to the remainder of the compound of Formula I, II,III, or IV (such as IVa-IVh) through two adjacent carbons, wherein saidC₃-C₅ carbocyclylene is optionally substituted with C₁-C₄ alkyl or C₁-C₃haloalkyl.

In certain embodiments, {circle around (T)} is C₃-C₆ carbocyclylene thatis attached to L and to the remainder of the compound of Formula I, II,III, or IV (such as any one of IVa-IVh) through two adjacent carbons,wherein the C₃-C₅ carbocyclylene is optionally substituted with methyl,ethyl or trifluoromethyl. In some embodiments, {circle around (T)} isC₃-C₆ carbocyclylene that is attached to L and to the remainder of thecompound of Formula I, II, III, or IV (such as any one of IVa-IVh)through two adjacent carbons.

In certain embodiments, {circle around (T)} is C₃-C₆ cycloalkyl that isattached to L and to the remainder of the compound of Formula I, II,III, or IV (such as any one of IVa-IVh) through two adjacent carbons,wherein the C₃-C₅ cycloalkyl is optionally substituted with methyl,ethyl or trifluoromethyl. In some embodiments, {circle around (T)} isC₃-C₆ cycloalkyl that is attached to L and to the remainder of thecompound of Formula I, II, III, or IV (such as any one of IVa-IVh)through two adjacent carbons.

In certain embodiments, {circle around (T)} is cyclopropyl optionallysubstituted with methyl or trifluoromethyl.

In certain embodiments, {circle around (T)} is C₆-C₈ bridged bicycliccarbocyclylene or C₆-C₈ bridged fused carbocyclylene that is attached toL and to the remainder of the compound of Formula I, II, III, or IV(such as any one of IVa-IVh) through two adjacent carbons.

In certain embodiments, {circle around (T)} is C₆-C₈ bridged bicycliccycloalkyl or C₆-C₈ bridged fused cycloalkyl that is attached to L andto the remainder of the compound of Formula I, II, III, or IV (such asany one of IVa-IVh) through two adjacent carbons.

In some embodiments, {circle around (T)} is T¹, T², T³, T⁴, T⁵, T⁸, T⁹,T¹⁰, T¹¹, or T¹². In certain embodiments, {circle around (T)} is T¹, T²,T³, T⁴, T⁹, T¹⁰, T¹¹ or T¹⁴. In some embodiments, {circle around (T)} isT¹, T², or T³, optionally substituted with 1-4 Z¹ groups which are thesame or different.

In some embodiments, T¹ is

In some embodiments, T² is

In some embodiments, T³ is

In some embodiments, T⁵ is

In some embodiments, T⁸ is

In some embodiments, T⁹ is

In some embodiments, T¹⁰ is

In some embodiments, T¹¹ is

In some embodiments, T¹² is

In other embodiments, {circle around (T)} is

In certain embodiments, T¹ is:

In certain embodiments, T² is:

In certain embodiments, T³ is:

In certain embodiments, {circle around (T)} is T², which is optionallysubstituted with 1-4 Z¹ groups, which are the same or different.

In certain embodiments, T² is:

In certain embodiments, {circle around (T)} is

In other embodiments, {circle around (T)} is

In other embodiments, {circle around (T)} is

In other embodiments, {circle around (T)} is

In certain embodiments, T² is:

In certain embodiments, T² is:

In certain embodiments, T² is:

(a stereoisomer of bicyclo[3.1.0]hexanylene).

In certain embodiments, J is J¹, J⁴, J⁵ or J⁸. In other embodiments, Jis J⁴. In certain embodiments, J is J⁵.

In further embodiments, J⁴ is

In other embodiments, J is

In other embodiments, J is

In other embodiments, J⁵ is

In certain embodiments, J is C₁-C₃ alkyl. In certain embodiments, J ismethyl or ethyl. In further other embodiments, J is —CH₂—CH₃.

In some embodiments, L is L¹, L², L³, L⁴, L⁵, L⁶, L⁷, L⁸ or L⁹. In oneembodiment, L is L¹, L², L³, L⁴, L⁵ or L⁶. In certain embodiments, L isL¹ or L².

In some embodiments, L is C₃-C₆ alkylene, substituted with 1-4 halogens.

In some embodiments, L is C₅ alkylene, substituted with two halogens. Insome embodiments, the halogens of L are each fluoro.

In certain embodiments, L is:

In certain other embodiments, L is

In some embodiments, L¹ is:

In some embodiments, L² is:

In some embodiments, L³ is

In some embodiments, L⁴ is

In some embodiments, L⁵ is

In some embodiments, L⁶ is

In some embodiments, L⁷ is

In some embodiments, L⁸ is

In some embodiments, L⁹ is

In other embodiments, L is

In further embodiments, L is

In further embodiments, L is

In still more embodiments, L is

In other embodiments, L is

In some embodiments, Q is Q¹, Q², Q³, Q⁴, Q⁵ or Q⁷

In some embodiments, Q¹ is

In some embodiments, Q² is

In some embodiments, Q³ is

In some embodiments, Q⁴ is

In some embodiments, Q⁵ is or

In some embodiments, Q⁷ is

In other embodiments, Q is

In certain embodiments, Q is Q¹. In certain other embodiments, Q isC₁-C₄ alkyl or C₃-6 carbocyclyl. In further embodiments, Q is

(i.e., t-butyl). In some embodiments, Q is t-butyl or C₅-C₆ cycloalkyl.

In certain embodiments, E is E¹, E², E³, or E⁴. In certain embodiments,E is E³.

In certain embodiments, E is C₁-C₃ alkyl optionally substituted with 1-3halogen atoms. In certain embodiments, E is difluoromethyl.

In certain other embodiments, E is

In some embodiments, E is

In other embodiments, E is

In other embodiments, E is

In other embodiments, E is

In certain embodiments, {circle around (U)} is bicyclic heteroaryl,optionally substituted with 1-4 W groups which are the same ordifferent.

In certain other embodiments, {circle around (U)} is

optionally substituted with 1-4 W groups, which are the same ordifferent.

In certain embodiments, {circle around (U)} is substituted with one Wgroup.

In some embodiments, {circle around (U)} is U¹, U³, U⁴, U⁵ or U⁶,wherein each U¹, U³, U⁴, U⁵ or U⁶ is optionally substituted with 1-3 Wat any substitutable position, and each W is independently W¹, W², W³,W⁴, W⁵, W⁶ or W⁷.

In certain embodiments, W¹ is oxo, halogen, —OR⁶, C₁-C₆ alkyl, —CN,—CF₃, —SR⁶, —C(O)₂R⁶, —C(O)N(R⁶)₂, —C(O)R⁶, —N(R⁶)C(O)R⁶, —SO₂(C₁-C₆alkyl), —S(O)(C₁-C₆ alkyl), C₃-C₈ carbocyclyl, C₃-C₈ cycloalkoxy, C₁-C₆haloalkyl, —N(R⁶)₂, —NR⁶(C₁-C₆ alkyl)O(C₁-C₆ alkyl), halo(C₁-C₆ alkoxy),—NR⁶SO₂R⁶, —SO₂N(R⁶)₂, —NHCOOR⁶, —NHCONHR⁶, C₆-C₁₀ aryl, 5-14 memberedheteroaryl, 4-10 membered heterocyclyl or —O(4-10 memberedheterocyclyl), wherein said W alkyl, carbocyclyl, cycloalkoxy,haloalkyl, haloalkoxy, aryl, heteroaryl, or heterocyclyl is optionallysubstituted with 1-4 Z^(1c) groups.

In certain embodiments, each R⁶ is independently H, C₆-C₁₀ aryl or C₁-C₆alkyl, wherein said aryl or alkyl is optionally substituted with 1 to 4substituents independently selected from halogen atoms, C₁-C₆ alkyl,C₆-C₁₀ aryl, C₃-C₈ carbocyclyl, 5-14 membered heteroaryl, 4-10 memberedheterocyclyl, halo(C₁-C₆ alkoxy), —OH, —O(C₁-C₆ alkyl), —SH, —S(C₁-C₆alkyl), —NH₂, —NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)₂, —C(O)(C₁-C₆ alkyl),—SO₂N(C₁-C₆ alkyl)₂, —NHCOO(C₁-C₆ alkyl), —NHCO(C₁-C₆ alkyl),—NHCONH(C₁-C₆ alkyl), —CO₂(C₁-C₆ alkyl), or —C(O)N(C₁-C₆ alkyl)₂.

In certain embodiments, W² is C₁-C₆ alkoxy substituted with a 5-14membered heteroaryl or C₆-C₁₀ aryl; wherein said heteroaryl or aryl issubstituted with 1-4 Z^(1c) groups.

In certain embodiments, W³ is a C₂-C₈ alkynyl group substituted with aC₆-C₁₀ aryl, C₃-C₈ carbocyclyl, C₁-C₈ alkyl, C₁-C₆ haloalkyl, 4-10membered heterocyclyl, or 5-14 membered heteroaryl group; wherein saidaryl, carbocyclyl, alkyl, haloalkyl, heterocyclyl, or heteroaryl groupis optionally substituted with 1-4 Z^(1c) groups.

In some embodiments, W⁴ is —SF₅.

In some embodiments, W⁵ is —O(C₂-C₆ alkyl)OR²² wherein R²² is a C₆-C₁₀aryl, 5-14 membered heteroaryl or 4-10 membered heterocyclyl group thatis optionally substituted with 1-4 Z^(1c) groups.

In certain embodiments, W is hydrogen, —O(C₁-C₃)alkyl, halogen or cyano.

In certain embodiments, W is methoxy.

In some embodiments, U¹ is

wherein each U¹ is optionally substituted with 1-2 Z¹ groups.

In some embodiments, U³ is

wherein each U³ is optionally substituted with 1-2 Z¹ groups.

In some embodiments, U⁴ is

wherein each U⁴ is optionally substituted with 1-2 Z¹ groups.

In some embodiments, U⁵ is

wherein each U⁵ is optionally substituted with 1-2 Z¹ groups.

In some embodiments, U⁶ is

wherein each U⁶ is optionally substituted with 1-2 Z¹ groups.

In some embodiments, U⁷ is

wherein each U⁷ is optionally substituted with 1-2 Z¹ groups.

In other embodiments, {circle around (T)} is optionally substituted withone or two W at any substitutable position, and each W is independentlyW¹, W², W³, W⁴, W⁵, W⁶ or W⁷ wherein (−) is

In other embodiments, {circle around (U)} is optionally substituted withone W at any substitutable position, and each W is independently W¹, W²,W³, W⁴, W⁵, W⁶ or W⁷ wherein {circle around (U)} is

In other embodiments, each W is independently W¹, W², W³, W⁴, W⁵, W⁶ orW⁷.

In some embodiments, W¹ is

In some embodiments, W² is

In some embodiments, W³ is

In some embodiments, W⁵ is

In some embodiments, W⁶ is

In some embodiments, W⁷ is

In other embodiments, W is

In certain embodiments, each W is independently halogen or C₁-C₄ alkoxy.

In a specific embodiment, J is methyl or ethyl; E is substituted with1-2 halogen atoms; L is substituted with 1-2-halogen atoms, and T isunsubstituted.

In a further embodiment, J is methyl or ethyl; E is C₁-C₃ haloalkyl; Lis C₅-alkyl or C₅-alkenyl.

In another embodiment, a compound of Formula (IV):

or a stereoisomer, or a mixture of stereoisomers, or a pharmaceuticallyacceptable salt thereof, is provided, wherein:

-   -   J is C₁-C₄ alkyl or C₃-C₆ carbocyclyl, wherein C₁-C₄ alkyl or        C₃-C₆ carbocyclyl is optionally substituted with halogen, —OH,        aryl or cyano;    -   {circle around (T)} is C₃-C₅ carbocyclylene that is attached to        L and to the remainder of the compound through two adjacent        carbons, wherein said C₃-C₅ carbocyclylene is optionally        substituted with C₁-C₄ alkyl, C₁-C₃ haloalkyl, halogen, —OH, or        cyano, or {circle around (T)} is C₅-C₈ bicyclic carbocyclylene        that is attached to L and to the remainder of the compound        through two adjacent carbons, or {circle around (T)} is C₃-C₆        carbocyclylene that is attached to L and to the remainder of the        compound of Formula IV through two adjacent carbons, wherein        said C₃-C₆ carbocyclene is optionally substituted with C₁-C₄        alkyl or C₁-C₃ haloalkyl;    -   L is C₃-C₆ alkylene, C₃-C₆ alkenylene or        —(CH₂)₃-cyclopropylene-, optionally substituted with 1-4        halogen, —OH, or cyano;    -   Q is C₂-C₄ alkyl or C₃-C₆ carbocyclyl optionally substituted        with C₁-C₃ alkyl, halogen, —OH, or cyano;    -   E is C₁-C₃ alkyl or C₂-C₃ alkenyl, optionally substituted with        C₁-C₃ alkyl, halogen, —OH, or cyano;    -   W is H, —OH, —O(C₁-C₃)alkyl, —O(C₁-C₃)haloalkyl, halogen or        cyano; and    -   Z^(2a) is H or C₁-C₃ alkyl, halogen, —OH, or cyano.

In a further embodiment of Formula (IV), J is C₁-C₃ alkyl.

In a further embodiment of Formula (IV), J is methyl or ethyl.

In a further embodiment of Formula (IV), {circle around (T)} is C₃-C₆carbocyclylene that is attached to L and to the remainder of thecompound of Formula IV through two adjacent carbons, wherein said C₃-C₆carbocyclene is optionally substituted with C₁-C₄ alkyl or C₁-C₃haloalkyl.

In a further embodiment of Formula (IV), {circle around (T)} is C₃-C₆carbocyclylene that is attached to L and to the remainder of thecompound of Formula IV through two adjacent carbons, wherein the C₃-C₆carbocyclene is optionally substituted with methyl, ethyl ortrifluoromethyl.

In a further embodiment of Formula (IV), {circle around (T)} iscyclopropylene.

In a further embodiment of Formula (IV), {circle around (T)} is C₆-C₈bridged bicyclic carbocyclylene or C₆-C₈ fused bicyclic carbocyclylenethat is attached to L and to the remainder of the compound of Formula IVthrough two adjacent carbons.

In a further embodiment of Formula (IV), L is C₃-C₆ alkylene,substituted with 1-4 halogens. In another embodiment of Formula (IV), Lis C₅ alkylene, substituted with two halogens. In some embodiments, thehalogens are each fluoro.

In a further embodiment of Formula (IV), L is C₃-C₆ alkylene.

In a further embodiment of Formula (IV), L is C₅ alkylene.

In a further embodiment of Formula (IV), Q is t-butyl or C₅-C₆carbocyclyl.

In a further embodiment of Formula (IV), Q is t-butyl.

In a further embodiment of Formula (IV), E is C₁-C₃ alkyl optionallysubstituted with 1-3 halogen atoms.

In a further embodiment of Formula (IV), E is difluoromethyl.

In a further embodiment of Formula (IV), W is hydrogen, —O(C₁-C₃)alkyl,halogen or cyano.

In a further embodiment of Formula (IV), W is methoxy.

In a further embodiment of Formula (IV), Z^(2a) is hydrogen or methyl.

In a further embodiment of Formula (IV), Z^(2a) is methyl.

There is further provided a compound selected from the group consistingof:

In one embodiment, a compound of Formula IVa, or a pharmaceuticallyacceptable salt thereof, is provided:

In one embodiment, a compound of Formula IVb: or a pharmaceuticallyacceptable salt thereof, is provided:

In one embodiment, a compound of Formula IVc, or a pharmaceuticallyacceptable salt thereof, is provided:

In one embodiment, a compound of Formula IVd, or a pharmaceuticallyacceptable salt thereof, is provided:

In one embodiment, a compound of Formula IVe, or a pharmaceuticallyacceptable salt thereof, is provided:

In one embodiment, a compound of Formula IVf, or a pharmaceuticallyacceptable salt thereof, is provided:

In one embodiment, a compound of Formula IVg, or a pharmaceuticallyacceptable salt thereof, is provided:

In one embodiment, a compound of Formula IVh, or a pharmaceuticallyacceptable salt thereof, is provided:

In one embodiment, a compound of any one of Formula IVa, IVb, IVc, IVd,IVe, IVf, IVg, or IVh, or a stereoisomer, or a mixture of stereoisomers,or a pharmaceutically acceptable salt thereof, is provided.

Methods of Treatment

One embodiment provides a method for treating a Flaviviridae viralinfection (e.g., an HCV viral infection) in a patient in need thereof(e.g., a mammal such as a human). The method includes administering acompound of Formula I, II III or IV (such as any one of IVa-IVh), or astereoisomer, or a mixture of stereoisomers, or a pharmaceuticallyacceptable salt thereof, to the patient.

One embodiment provides a method for inhibiting the proliferation of theHCV virus, treating HCV infection or delaying the onset of HCV symptomsin a patient in need thereof (e.g., a mammal such as a human). Themethod includes administering a compound of Formula I, II, III or IV(such as any one of IVa-IVh), or a stereoisomer, or a mixture ofstereoisomers, or a pharmaceutically acceptable salt thereof, to thepatient.

One embodiment provides a compound of Formula I, II, III or IV (such asany one of IVa-IVh), or a stereoisomer, or a mixture of stereoisomers,or a pharmaceutically acceptable salt thereof for use in medical therapy(e.g., for use in treating a Flaviviridae viral infection (e.g., an HCVviral infection) or the proliferation of the HCV virus or delaying theonset of HCV symptoms in a patient (e.g., a mammal such as a human)).

One embodiment provides a compound of Formula I, II, III, or IV (such asany one of IVa-IVh) or a stereoisomer, or a mixture of stereoisomers, ora pharmaceutically acceptable salt thereof for use in the manufacture ofa medicament for treating a Flaviviridae viral infection (e.g., an HCVviral infection) or the proliferation of the HCV virus or delaying theonset of HCV symptoms in a patient in need thereof (e.g., mammal such asa human).

One embodiment provides a compound of Formula I, II, III, or IV (such asany one of IVa-IVh), or a stereoisomer, or a mixture of stereoisomers,or a pharmaceutically acceptable salt thereof, for use in theprophylactic or therapeutic treatment of the proliferation of aFlaviviridae virus, an HCV virus or for use in the therapeutic treatmentof delaying the onset of HCV symptoms.

One embodiment provides a compound of Formula I, II, III or IV (such asany one of IVa-IVh) or a stereoisomer, or a mixture of stereoisomers, ora pharmaceutically acceptable salt thereof, for use in the prophylacticor therapeutic treatment of a Flaviviridae virus infection (e.g., an HCVvirus infection).

One embodiment provides the use of a compound of Formula I, II, III orIV (such as any one of IVa-IVh), or a stereoisomer, or a mixture ofstereoisomers, or a pharmaceutically acceptable salt thereof, for themanufacture of a medicament for a Flaviviridae virus infection (e.g., anHCV virus infection) in a mammal (e.g., a human).

In certain embodiments, a method of treating chronic hepatitis Cinfection is provided. The method includes administering to a patient inneed thereof, a compound of Formula I, II III or IV (such as any one ofIVa-IVh), or a stereoisomer, or a mixture of stereoisomers, or apharmaceutically acceptable salt thereof, to the patient.

In certain embodiments, a method of treating hepatitis C infection intreatment-naïve patients is provided. The method includes administeringto a treatment-naïve patient, a compound of Formula I, II III or IV(such as any one of IVa-IVh), or a stereoisomer, or a mixture ofstereoisomers, or a pharmaceutically acceptable salt thereof.

In certain embodiments, a method of treating hepatitis C infection intreatment-experienced patients is provided. The method includesadministering to a treatment-experienced patient, a compound of FormulaI, II III or IV (such as any one of IVa-IVh), or a stereoisomer, or amixture of stereoisomers, or a pharmaceutically acceptable salt thereof.

In certain embodiments, a method of treating hepatitis C infection in aninterferon ineligible or an interferon intolerant patient is provided.The method includes administering, a compound of Formula I, II III or IV(such as any one of IVa-IVh), or a stereoisomer, or a mixture ofstereoisomers, or a pharmaceutically acceptable salt thereof, to thepatient.

In certain embodiments, the methods of treatment described hereininclude administering the compound of Formula I, II III or IV (such asany one of IVa-IVh), or a stereoisomer, or a mixture of stereoisomers,or a pharmaceutically acceptable salt thereof, to the patient for afixed period of duration. In some embodiments, the fixed period ofduration is 4 weeks, 6 weeks, 8 weeks, 10 weeks or 12 weeks. In otherembodiments, the fixed period of duration is not more than 12 weeks.

In some embodiments, the compound is administered for about 12 weeks. Infurther embodiments, the compound is administered for about 12 weeks orless, for about 10 weeks or less, for about 8 weeks or less, for about 6weeks or less, or for about 4 weeks or less.

The compound may be administered once daily, twice daily, once everyother day, two times a week, three times a week, four times a week, orfive times a week.

In certain embodiments, the methods of treatment described hereinincludes administering a compound of Formula I, II III or IV (such asany one of IVa-IVh), or a stereoisomer, or a mixture of stereoisomers,or a pharmaceutically acceptable salt thereof, to is infected with HCVgenotype (GT) 1, 2, 3, 4, 5, or 6 (i.e., a method for treating a GT 1,2, 3, 4, 5, or 6 HCV infection).

One embodiment provides a method for treating an HCV infection in apatient in need thereof (e.g., a mammal such as a human), wherein thepatient is infected with HCV genotype 1. The method includesadministering a compound of Formula I, II III or IV (such as any one ofIVa-IVh), or a stereoisomer, or a mixture of stereoisomers, or apharmaceutically acceptable salt thereof, to the patient.

One embodiment provides a method for treating an HCV infection in apatient in need thereof (e.g., a mammal such as a human), wherein thepatient is infected with HCV genotype 2. The method includesadministering a compound of Formula I, II III or IV (such as any one ofIVa-IVh), or a stereoisomer, or a mixture of stereoisomers, or apharmaceutically acceptable salt thereof, to the patient.

One embodiment provides a method for treating an HCV infection in apatient in need thereof (e.g., a mammal such as a human), wherein thepatient is infected with HCV genotype 3. The method includesadministering a compound of Formula I, II III or IV (such as any one ofIVa-IVh), or a stereoisomer, or a mixture of stereoisomers, or apharmaceutically acceptable salt thereof, to the patient.

One embodiment provides a method for treating an HCV infection in apatient in need thereof (e.g., a mammal such as a human), wherein thepatient is infected with HCV genotype 4. The method includesadministering a compound of Formula I, II III or IV (such as any one ofIVa-IVh), or a stereoisomer, or a mixture of stereoisomers, or apharmaceutically acceptable salt thereof, to the patient.

One embodiment provides a method for treating an HCV infection in apatient in need thereof (e.g., a mammal such as a human), wherein thepatient is infected with HCV genotype 5. The method includesadministering a compound of Formula I, II III or IV (such as any one ofIVa-IVh), or a stereoisomer, or a mixture of stereoisomers, or apharmaceutically acceptable salt thereof, to the patient.

One embodiment provides a method for treating an HCV infection in apatient in need thereof (e.g., a mammal such as a human), wherein thepatient is infected with HCV genotype 6. The method includesadministering a compound of Formula I, II III or IV (such as any one ofIVa-IVh), or a stereoisomer, or a mixture of stereoisomers, or apharmaceutically acceptable salt thereof, to the patient.

In the methods of treatment described herein, the administering stepincludes administering a therapeutically effective amount of a compoundof Formula I, II III or IV (such as any one of IVa-IVh), or astereoisomer, or a mixture of stereoisomers, or a pharmaceuticallyacceptable salt thereof, to the patient in need of treatment.

In certain embodiments, methods of inhibiting the activity of HCV areprovided. Such methods include the step of treating a sample suspectedof containing HCV with a compound or composition disclosed herein.

In one embodiment, compounds disclosed herein act as inhibitors of HCV,as intermediates for such inhibitors or have other utilities asdescribed below.

In certain embodiments, compounds binding in the liver may bind withvarying degrees of reversibility.

In one embodiment, a method for treating HCV includes adding a compounddisclosed herein to the sample. The addition step comprises any methodof administration as described above.

If desired, the activity of HCV after application of the compound can beobserved by any method including direct and indirect methods ofdetecting HCV activity. Quantitative, qualitative, and semiquantitativemethods of determining HCV activity are all contemplated. Typically oneof the screening methods described above are applied, however, any othermethod such as observation of the physiological properties of a livingorganism are also applicable.

Many organisms contain HCV. The compounds of this invention are usefulin the treatment or prophylaxis of conditions associated with HCVactivation in animals or in humans.

Pharmaceutical Formulations

“Pharmaceutically-acceptable” means suitable for use in pharmaceuticalpreparations, generally considered as safe for such use, officiallyapproved by a regulatory agency of a national or state government forsuch use, or being listed in the U. S. Pharmacopoeia or other generallyrecognized pharmacopoeia for use in animals, and more particularly inhumans.

“Pharmaceutically-acceptable carrier” refers to a diluent, adjuvant,excipient, or carrier, or other ingredient which ispharmaceutically-acceptable and with which a compound of the inventionis administered.

The compounds of this invention are formulated with conventionalcarriers (e.g., inactive ingredient or excipient material), which willbe selected in accord with ordinary practice. Tablets will containexcipients including glidants, fillers, binders and the like. Aqueousformulations are prepared in sterile form, and when intended fordelivery by other than oral administration generally will be isotonic.All formulations will optionally contain excipients such as those setforth in the Handbook of Pharmaceutical Excipients (1986). Excipientsinclude ascorbic acid and other antioxidants, chelating agents such asEDTA, carbohydrates such as dextrin, hydroxyalkylcellulose,hydroxyalkylmethylcellulose, stearic acid and the like. One embodimentprovides the formulation as a solid dosage form including a solid oraldosage form. The pH of the formulations ranges from about 3 to about 11,but is ordinarily about 7 to 10.

While it is possible for the active ingredients to be administered aloneit may be preferable to present them as pharmaceutical formulations(compositions). The formulations, both for veterinary and for human use,of the invention comprise at least one active ingredient, as abovedefined, together with one or more acceptable carriers therefor andoptionally other therapeutic ingredients. The carrier(s) must be“acceptable” in the sense of being compatible with the other ingredientsof the formulation and physiologically innocuous to the recipientthereof.

The formulations include those suitable for the foregoing administrationroutes. The formulations may conveniently be presented in unit dosageform and may be prepared by any of the methods well known in the art ofpharmacy. Techniques and formulations generally are found in Remington'sPharmaceutical Sciences (Mack Publishing Co., Easton, Pa.). Such methodsinclude the step of bringing into association the active ingredient withinactive ingredients (e.g., a carrier, pharmaceutical excipient, etc.)which constitutes one or more accessory ingredients. In general theformulations are prepared by uniformly and intimately bringing intoassociation the active ingredient with liquid carriers or finely dividedsolid carriers or both, and then, if necessary, shaping the product.

In certain embodiments, formulations suitable for oral administrationare presented as discrete units such as capsules, cachets or tabletseach containing a predetermined amount of the active ingredient.

In certain embodiments, the pharmaceutical formulations include one ormore compounds of the invention together with one or morepharmaceutically acceptable carriers or excipients and optionally othertherapeutic agents. Pharmaceutical formulations containing the activeingredient may be in any form suitable for the intended method ofadministration. When used for oral use for example, tablets, troches,lozenges, aqueous or oil suspensions, dispersible powders or granules,emulsions, hard or soft capsules, syrups or elixirs may be prepared.Compositions intended for oral use may be prepared according to anymethod known to the art for the manufacture of pharmaceuticalcompositions and such compositions may contain one or more agentsincluding sweetening agents, flavoring agents, coloring agents andpreserving agents, in order to provide a palatable preparation. Tabletscontaining the active ingredient in admixture with non-toxicpharmaceutically acceptable excipient which are suitable for manufactureof tablets are acceptable. These excipients may be, for example, inertdiluents, such as calcium or sodium carbonate, lactose, lactosemonohydrate, croscarmellose sodium, povidone, calcium or sodiumphosphate; granulating and disintegrating agents, such as maize starch,or alginic acid; binding agents, such as cellulose, microcrystallinecellulose, starch, gelatin or acacia; and lubricating agents, such asmagnesium stearate, stearic acid or talc. Tablets may be uncoated or maybe coated by known techniques including microencapsulation to delaydisintegration and adsorption in the gastrointestinal tract and therebyprovide a sustained action over a longer period. For example, a timedelay material such as glyceryl monostearate or glyceryl distearatealone or with a wax may be employed.

The amount of active ingredient that is combined with the inactiveingredients to produce a dosage form will vary depending upon the hosttreated and the particular mode of administration. For example, in someembodiments, a dosage form for oral administration to humans containsapproximately 1 to 1000 mg of active material formulated with anappropriate and convenient amount of carrier material (e.g., inactiveingredient or excipient material). In certain embodiments, the carriermaterial varies from about 5 to about 95% of the total compositions(weight: weight). In some embodiments, the pharmaceutical compositionsdescribed herein contain about 1 to 800 mg, 1 to 600 mg, 1 to 400 mg, 1to 200 mg, 1 to 100 mg or 1 to 50 mg of the compound of Formula I, II,111 or IV (such as any one of IVa-IVh), or a stereoisomer, or a mixtureof stereoisomers, or a pharmaceutically acceptable salt thereof. In someembodiments, the pharmaceutical compositions described herein containnot more than about 400 mg of the compound of Formula I, II, III or IV(such as any one of IVa-IVh), or a stereoisomer, or a mixture ofstereoisomers, or a pharmaceutically acceptable salt thereof. In someembodiments, the pharmaceutical compositions described herein containabout 100 mg of the compound of Formula I, II, III, or IV (such as anyone of IVa-IVh), or a stereoisomer, or a mixture of stereoisomers, or apharmaceutically acceptable salt thereof.

It should be understood that in addition to the ingredients particularlymentioned above the formulations disclosed herein may include otheragents conventional in the art having regard to the type of formulationin question, for example those suitable for oral administration mayinclude flavoring agents.

Veterinary compositions comprising at least one active ingredient asabove defined together with a veterinary carrier are further provided.

Veterinary carriers are materials useful for the purpose ofadministering the composition and may be solid, liquid or gaseousmaterials which are otherwise inert or acceptable in the veterinary artand are compatible with the active ingredient. These veterinarycompositions may be administered orally, parenterally or by any otherdesired route.

Effective dose of active ingredient depends at least on the nature ofthe condition being treated, toxicity, whether the compound is beingused prophylactically (lower doses), the method of delivery, and thepharmaceutical formulation, and will be determined by the clinicianusing conventional dose escalation studies.

Routes of Administration

One or more compounds of Formulas I, II, III, or IV (such as any one ofIVa-IVh) (herein referred to as the active ingredients), or apharmaceutically acceptable salt thereof, are administered by any routeappropriate to the condition to be treated. Suitable routes includeoral, rectal, nasal, topical (including buccal and sublingual), vaginaland parenteral (including subcutaneous, intramuscular, intravenous,intradermal, intrathecal and epidural), and the like. It will beappreciated that the preferred route may vary with for example thecondition of the recipient. An advantage of the compounds of thisinvention is that they are orally bioavailable and can be dosed orally.Accordingly, in one embodiment, the pharmaceutical compositionsdescribed herein are oral dosage forms. In certain embodiments, thepharmaceutical compositions described herein are oral solid dosageforms.

One skilled in the art will recognize that substituents and othermoieties of the compounds of the generic formula herein should beselected in order to provide a compound which is sufficiently stable toprovide a pharmaceutically useful compound which can be formulated intoan acceptably stable pharmaceutical composition. Compounds which havesuch stability are contemplated as falling within the scope of thepresent invention. It should be understood by one skilled in the artthat any combination of the definitions and substituents described aboveshould not result in an inoperable species or compound.

Combination Therapy

In yet another embodiment, the present application disclosespharmaceutical compositions comprising a compound of Formulas I, II,III, or IV (such as any one of IVa-IVh), or a pharmaceuticallyacceptable salt thereof, in combination with at least one additionaltherapeutic agent (i.e., active ingredient), and a pharmaceuticallyacceptable carrier or excipient. In certain embodiments, additionaltherapeutic agents include additional antiviral agents.

The additional therapeutic agent used in combination with the compoundsdescribed herein includes, without limitation, any agent having atherapeutic effect when used in combination with the compound of thepresent invention. Such combinations are selected based on the conditionto be treated, cross-reactivities of ingredients and pharmaco-propertiesof the combination. For example, in certain embodiments, the therapeuticagent used in combination with the compounds of Formulas I, II, III, orIV (such as any one of IVa-IVh) include, without limitation, one of moreof the following: interferons, ribavirin analogs, NS3 proteaseinhibitors, NS5a inhibitors, NS5b inhibitors, alpha-glucosidase 1inhibitors, hepatoprotectants, non-nucleoside inhibitors of HCV,nucleoside analogues, and other drugs for treating HCV infection. Insome embodiments, the additional therapeutic agents include, withoutlimitation, NS3 protease inhibitors, NS5a inhibitors, and/or NS5binhibitors. In some embodiments, a pharmaceutical composition includinga compound of Formulas I, II, III, or IV (such as any one of IVa-IVh),or a pharmaceutically acceptable salt thereof and one or more of an NS3protease inhibitor, an NS5a inhibitor, and/or an NS5b inhibitor isprovided. In some embodiments, a pharmaceutical composition including acompound of Formulas I, II, III, or IV (such as any one of IVa-IVh), ora pharmaceutically acceptable salt thereof and one or more of an NS5ainhibitor and/or an NS5b inhibitor is provided. In certain embodiments,pharmaceutical compositions is provided which includes a compound ofFormulas I, II, III, or IV (such as any one of IVa-IVh) and one or moreadditional antiviral agents, wherein the additional antiviral agent isnot an interferon, ribavirin, or a ribavirin analogue. In furtherembodiments, pharmaceutical compositions is provided which includes acompound of Formulas I, II, III, or IV (such as any one of IVa-IVh), ora stereoisomer, or a mixture of stereoisomers, and one or moreadditional antiviral agents, wherein the additional antiviral agent isnot ribavirin or a ribavirin analogue.

In certain embodiments, the compounds disclosed herein are combined withone or more other active ingredients (e.g., one or more additionalantiviral agents) in a unitary dosage form for simultaneous orsequential administration to a patient. The combination therapy may beadministered as a simultaneous or sequential regimen. When administeredsequentially, the combination is administered in two or moreadministrations. In certain embodiments, the active ingredients are: (1)co-formulated and administered or delivered simultaneously in a combinedpharmaceutical composition; (2) delivered by alternation or in parallelas separate pharmaceutical composition; or (3) by some other regimen.When delivered in alternation therapy, the active ingredients areadministered or delivered sequentially, e.g., in separate tablets, pillsor capsules, or by different injections in separate syringes. Ingeneral, during alternation therapy, an effective dosage of each activeingredient is administered sequentially, i.e. serially, whereas incombination therapy, effective dosages of two or more active ingredientsare administered together.

Exemplary inferferons include, without limitation, pegylated rIFN-alpha2b (PEG-Intron), pegylated rIFN-alpha 2a (Pegasys), rIFN-alpha 2b(Intron A), rIFN-alpha 2a (Roferon-A), interferon alpha (MOR-22, OPC-18,Alfaferone, Alfanative, Multiferon, subalin), interferon alfacon-1(Infergen), interferon alpha-n1 (Wellferon), interferon alpha-n3(Alferon), interferon-beta (Avonex, DL-8234), interferon-omega (omegaDUROS, Biomed 510), albinterferon alpha-2b (Albuferon), IFN alpha XL,BLX-883 (Locteron), DA-3021, glycosylated interferon alpha-2b (AVI-005),PEG-Infergen, PEGylated interferon lambda (PEGylated IL-29), orbelerofon, IFN alpha-2b XL, rIFN-alpha 2a, consensus IFN alpha,infergen, rebif, pegylated IFN-beta, oral interferon alpha, feron,reaferon, intermax alpha, r-IFN-beta, and infergen+actimmune.

Exemplary ribavarin analogs include, without limitation, ribavirin(Rebetol, Copegus), levovirin VX-497, and taribavirin (Viramidine).

Exemplary NS5A inhibitors include, without limitation, ledipasvir(GS-5885), GS-5816, JNJ-47910382, daclatasvir (BMS-790052), ABT-267,MK-8742, EDP-239, IDX-719, PPI-668, GSK-2336805, ACH-3102, A-831, A-689,AZD-2836 (A-831), AZD-7295 (A-689), and BMS-790052.

Exemplary NS5B inhibitors include, without limitation, polymeraseinhibitor is sofosbuvir (GS-7977), tegobuvir (GS-9190), GS-9669,TMC647055, ABT-333, ABT-072, setrobuvir (ANA-598), filibuvir(PF-868554), VX-222, IDX-375, IDX-184, IDX-102, BI-207127,valopicitabine (NM-283), R1626, PSI-6130 (R1656), PSI-7851, BCX-4678,nesbuvir (HCV-796), BILB 1941, MK-0608, NM-107, R7128, VCH-759,GSK625433, XTL-2125, VCH-916, JTK-652, MK-3281, VBY-708, A848837,GL59728, A-63890, A-48773, A-48547, BC-2329, BMS-791325, and BILB-1941.

Exemplary NS3 protease inhibitors include, without limitation, GS-9451,GS-9256, simeprevir (TMC-435), ABT-450, boceprevir (SCH-503034),narlaprevir (SCH-900518), vaniprevir (MK-7009), MK-5172, danoprevir(ITMN-191), sovaprevir (ACH-1625), neceprevir (ACH-2684), Telaprevir(VX-950), VX-813, VX-500, faldaprevir (BI-201335), asunaprevir(BMS-650032), BMS-605339, VBY-376, PHX-1766, YH5531, BILN-2065, andBILN-2061.

Exemplary alpha-glucosidase 1 inhibitors include, without limitation,celgosivir (MX-3253), Miglitol, and UT-231B.

Exemplary hepatoprotectants include, without limitation, IDN-6556, ME3738, MitoQ, and LB-84451.

Exemplary non-nucleoside inhibitors of HCV include, without limitation,benzimidazole derivatives, benzo-1,2,4-thiadiazine derivatives, andphenylalanine derivatives.

Exemplary nucleoside analogues include, without limitation, ribavirin,viramidine, levovirin, a L-nucleoside, or isatoribine and saidinterferon is α-interferon or pegylated interferon.

Exemplary other drugs for treating HCV infection include, withoutlimitation, imiquimod, 852A, GS-9524, ANA-773, ANA-975, AZD-8848(DSP-3025), PF-04878691, and SM-360320, cyclophillin inhibitors (e.g.,DEBIO-025, SCY-635, or NIM811) or HCV IRES inhibitors (e.g., MCI-067).;emericasan (IDN-6556), ME-3738, GS-9450 (LB-84451), silibilin, or MitoQ.BAS-100, SPI-452, PF-4194477, TMC-41629, GS-9350, GS-9585, androxythromycin.

Additional exemplary other drugs for treating HCV infection include,without limitation, zadaxin, nitazoxanide (alinea), BIVN-401 (virostat),DEBIO-025, VGX-410C, EMZ-702, AVI 4065, bavituximab, oglufanide, PYN-17,KPE02003002, actilon (CPG-10101), KRN-7000, civacir, GI-5005, ANA-975(isatoribine), XTL-6865, ANA 971, NOV-205, tarvacin, EHC-18, and NIM811.

Still further exemplary other drugs for treating HCV infection include,without limitation, thymosin alpha 1 (Zadaxin), nitazoxanide (Alinea,NTZ), BIVN-401 (virostat), PYN-17 (altirex), KPE02003002, actilon(CPG-10101), GS-9525, KRN-7000, civacir, GI-5005, XTL-6865, BIT225,PTX-111, ITX2865, TT-033i, ANA 971, NOV-205, tarvacin, EHC-18, VGX-410C,EMZ-702, AVI 4065, BMS-650032, Bavituximab, MDX-1106 (ONO-4538),Oglufanide, FK-788, VX-497 (merimepodib), DEBIO-025, ANA-975(isatoribine), XTL-6865, or NIM811.

General Synthetic Procedures

The schemes, procedures, and examples provided herein describe thesynthesis of compounds disclosed herein as well as intermediates used toprepare the compounds. It is to be understood that individual stepsdescribed herein may be combined. It is also to be understood thatseparate batches of a compound may be combined and then carried forth inthe next synthetic step.

The following schemes describe methods that are useful for preparingcompounds disclosed herein.

L_(F) is a “linker fragment,” (that is to say, a precursor to L) whereinan attached unsaturated carbon-carbon bond (e.g. alkene or alkyne) atthe portion of L_(F) distal to {circle around (T)} facilitates, as anon-limiting example, a metal catalyzed reaction that results in theconnection of L_(F) to U to form an L group. Non-limiting examples ofmetal catalyzed reactions that result in such a connection include Rucatalyzed ring closing metathesis or a Pd catalyzed cross couplingreaction (e.g. Negishi, Heck, or Sonagashira couplings).

¹H Nuclear magnetic resonance (NMR) spectra were in all cases consistentwith the proposed structures. Characteristic chemical shifts (6) aregiven in parts-per-million downfield from tetramethylsilane usingconventional abbreviations for designation of major peaks: e.g. s,singlet; d, doublet; t, triplet; q, quartet; m, multiplet; br, broad.The following abbreviations have been used for common solvents used innuclear magnetic resonance experiments: CDCl₃, deuterochloroform; CD₃OD,perdeuteromethanol; CD₃CN, perdeuteroacetonitrile; d₆-DMSO,perdeuterodimethylsulfoxide. Mass spectra were obtained using ThermoScientific or Agilent Technologies mass spectrometers equipped withelectrospray ionisation (ESI). Masses are reported as ratios of mass tocharge (m/z) of, for example, an ion of the compound (represented by[M]⁺), an ion formed from the compound with another ion, such as ahydrogen ion (represented by [M+H]⁺), a sodium ion (represented by[M+Na]⁺), an ion formed from the compound by losing an ion, such as thedeprotonated compound (represented by [M−H]⁻), etc. Analytical HPLCmeasurements were performed on Agilent Technologies Series 1100 HPLCusing Phenomenex Kinetex C18, 2.6 um 100 Å, 4.6×100 mm column with anelution program of 2% Solvent B for 0.55 min, gradient to 98% solvent Bover 8 min which is maintained at 98% solvent B for 0.40 min beforereturning to 2% solvent B over 0.02 min and maintaining at 2% solvent Bfor 2.03 min at a flow rate of 1.5 mL/min (Solvent A=MiliQ filteredH₂O+0.1% TFA, Solvent B=MeCN+0.1% TFA). The term “thin layerchromatography (TLC)” refers to silica gel chromatography using silicagel 60 F₂₅₄ plates. The retention factor (“R_(f)”) of a compound is thedistance traveled by a compound divided by the distance traveled by thesolvent front on a TLC plate. Terms such as “early eluting” and “lateeluting” refer to the order in which a compound elutes or is recoveredfrom a solid stationary phase/liquid solvent mobile phase basedchromatography method (e.g. normal phase silica gel chromatography orreverse phase high pressure liquid chromatography (HPLC)).

Scheme 1 demonstrates a general route to S1-3, where J, R¹, R, M, L, T,U, W and Q are as defined herein, Z^(2a) is as defined in Formula IV orIII, or is Z² as defined in Formula I or II. In scheme 1, esterintermediate S1-1 is hydrolyzed with a base such as lithium hydroxidewhen R is C₁-C₃ alkyl (e.g., methyl), or with acid such astrifluoroacetic acid when R is tert-butyl. The product of the esterhydrolysis is then coupled to an intermediate S1-2 through a couplingreaction (e.g. using a peptide coupling agent such as HATU and a basesuch as DIPEA) to generate compounds of the general structure S1-3.

Scheme 2 shows a general synthesis of an intermediate S2-6 where U, W,R¹, J, and Q are as defied herein. In scheme 2, an appropriatelysubstituted and protected proline species S2-2 undergoes anetherification reaction such as S_(N)Ar (e.g. treatment with Cs₂CO₃ andS2-1 where R² is H and LG² is halogen), S_(N)2 (e.g. preconversion ofS2-2 to a brosylate (R² is Bs) followed by treatment with S2-1 where LG²is —OH and base such as DABCO), Mitsunobu reaction (e.g. treatment ofS2-2 with DIAD and triphenylphosphine followed by S2-1 where LG² is —OH)or metal catalyzed cross coupling reaction (LG² is halogen, R² is H) togenerate intermediate S2-3. Intermediate S2-3 is deprotected (e.g. 4 NHCl in dioxane when PG is Boc) to make intermediate S2-4. Amide bondformation via activation of the carboxylic acid of S2-5 using peptidecoupling agents or other carboxylic acid activation methods prior totreatment of S2-4 provides intermediate S2-6.

Scheme 3 shows a general synthesis of intermediate S3-6 whereL_(F)-CH₂—CH₂ is L, and U, W, R¹, J, Q, M, T, and L are as defiedherein. In scheme 3, an intermediate S3-1 is coupled via amide bondformation reaction to an intermediate S3-2 to provide intermediate S3-3.Metal catalyzed cross-coupling (e.g. Suzuki reaction using potassiumvinyltrifluoroborate, Et₃N, Pd(dppf)Cl₂) to give S3-4, followed by ringclosing metathesis (e.g. Zhan 1B) to give S3-5, followed by reduction ofthe double bond (e.g. H₂, 10% Pd/C) provides intermediate S3-6.

Scheme 4 shows a general synthesis of an intermediate S4-5 whereL_(F)-CH₂—CH₂ is L, and U, W, R¹, J, Q, Q and L are as defied herein. Inscheme 4, intermediate S4-1 is protected with a protecting group such asBoc. S4-1 undergoes a transition metal catalyzed cross coupling (e.g.Sonogashira coupling) to an intermediate S4-2 to provide intermediateS4-3. The triple bond of intermediate S4-3 is reduced to a single bondby hydrogenation (e.g. H₂, catalytic 10% Pd/C) to give intermediateS4-4. Deprotection of the Boc-amine followed by coupling under basicconditions (e.g. triethylamine) provides intermediate S4-5.

Scheme 5 shows a general synthesis of an intermediate S5-9 whereL_(F)-CH₂—CH₂ is L, and U, W, R¹, J, Q, T and L are as defied herein. Inscheme 5 intermediate S5-1 undergoes a metal catalyzed cross coupling(such as Sonogashira reaction) with an intermediate S5-2 to provideintermediate S5-3. The triple bond of intermediate S5-3 is reduced to asingle bond under appropriate conductions such as by hydrogenation (e.g.using H₂ over catalytic 10% Pd/C) to give intermediate S5-4.Deprotection of the alcohol to provide S5-5, followed by activation(e.g. DSC under basic conditions, e.g. triethylamine) providesintermediate S5-6. Coupling of S5-6 and S5-7 under basic conditionsprovides S5-8. Deprotection of the proline nitrogen (e.g. HCl in dioxanewhen PG=Boc) followed by a macrolactamization (e.g. coupling agent suchas HATU under basic conditions) provides intermediate S5-9.

Scheme 6 shows a general synthesis of the intermediates S6-6 and S6-7where U, R¹, J, Q, M, T and L are as defied herein. In scheme 6intermediate S6-1, W is OPG, where PG is a protecting group. S6-1 isfirst deprotected to give intermediate S6-2. Alkylation of intermediateS6-2 with an appropriate electrophile such as S6-4 provides intermediateS6-6. Reaction of S6-2 with triflic anyhydride provides S6-3, which thenundergoes metal catalyzed cross coupling with an appropriatenucleophilic coupling partner such as S6-5 (e.g. Sonagashira or Suzukireaction) to provide intermediate S6-7.

Scheme 7 shows a general synthesis of intermediate S7-13 whereL_(F)-CH₂—CH₂—CF₂ is L, and W, R¹, J, Q, M, and T are as defied herein.In S7-13, L is C₁-C₃ alkyl. In Scheme 7, intermediate S7-1 firstundergoes lithium halogen exchange and then is treated with intermediateS7-2 to generate intermediate S7-3, which is then condensed withintermediate S7-4 to provide quinoxaline intermediate S7-5. Halogenationof S7-5 (e.g. POCl₃) provides intermediate S7-6. Intermediate S7-6 isattached via an ether formation to intermediate S7-7 through an S_(N)Arreaction (e.g. Cs₂CO₃) to generate intermediate S7-8. Deprotection ofthe N-PG of intermediate S7-8 provides S7-10. An amide bond couplingreaction of intermediate S7-9 and intermediate S7-10 (e.g. EDC and HOBT,or HATU, NMM, DIPEA) provides intermediate S7-11. Ring closingmetathesis of S7-11 generates intermediate S7-12. Reduction of thedouble bond (e.g. hydrogenation over palladium on carbon) providesintermediate S7-13.

Scheme 8 shows a general syntheses of intermediate S8-5 wherein anappropriately protected 4-oxo proline S8-1 is reacted with Bredereck'sreagent to generate enaminone S8-2. Addition of an organometallicspecies provides enone S8-3, which undergoes reduction to hydroxylintermediate S8-4 in a stereoselective manner (e.g. Luche reduction orCBS reduction). Subsequent olefin reduction gives 3-substituted hydroxyproline intermediate S8-5.

Scheme 9 shows a general synthesis of intermediate S9-3 wherein a vinyltriflate S9-1 (prepared for example, by methods in Kamenecka, T. M., etal. Tetrahedron Letters, 2001, 8571) undergoes metal catalyzed crosscoupling (e.g. Negishi coupling) to generate intermediate S9-2.Hydroboration and subsequent oxidation of intermediate S9-2 providesintermediate S9-3.

Scheme 10 shows a general synthesis of substituted sulfonamideintermediate S10-3. Tert-butyl cyclopropylsulfonylcarbamate S10-1 isdeprotonated (e.g. n-BuLi) and reacted with an electrophile (e.g. alkylhalide) to give the protected substituted sulfonamide intermediateS10-2, which is then deprotected (e.g. 4 N HCl in dioxane) to provideintermediate S10-3.

Scheme 11 shows a general synthesis of an intermediate S11-3 where E isas defined herein. In Scheme 11, a sulfonamide S11-1 is coupled to aprotected amino acid S11-2 using a coupling agent such as CDI and a basesuch as DBU.

Scheme 12 shows a general synthesis of intermediates S12-10 and S12-17,where L_(F) is C₁-C₃ alkylene. In Scheme 12, both syntheses begin withthe monoprotection of intermediate S12-1 to produce S12-2, followed byoxidation (e.g. Swern oxidation) to provide intermediate S12-3.Enantioselective alpha chlorination (e.g. organocatalyst S12-4 and NCS)provides chloroaldehyde S12-5. Reaction of S12-5 with abis-zinciomethane derivative (e.g. Nysted's reagent) providescyclopropane intermediate S12-6. Intermediate S12-6 is orthogonallyprotected to provide intermediate S12-7. Deprotection of —OPG of S12-7provides intermediate S12-8, which is subsequently dehydrated (e.g.Grieco's reagent) to intermediate S12-9 and finally O-PG² is removed toafford intermediate S12-10. Intermediate S12-6 is alternatively beactivated (e.g. DSC and a base such as pyridine) to provide intermediateS12-11 which is coupled to intermediate S12-12 to provide carbamateintermediate S12-13. Intermediate S12-13 is deprotected to giveintermediate S12-14, which is then oxidized (e.g. Swern oxidation) toprovide aldehyde intermediate S12-15. Olefination (e.g. Wittig reaction)of intermediate S12-15 provides intermediate S12-16. Ester hydrolysis(e.g. LiOH when R is methyl, TFA when R=tert-butyl) affords intermediateS12-17.

Scheme 13 shows a general synthesis of intermediate S13-5 where Q and Tare as defined herein and L_(F) is C₁-C₃ alkylene. Activation ofintermediate S13-1 (e.g. DSC) followed by carbamate formation betweenintermediate S13-2 and amino acid ester intermediate S13-3 under basicconditions gives ester intermediate S13-4. Ester hydrolysis (e.g. LiOHwhen R=methyl or TFA when R=tert-butyl) provides intermediate S13-5.

Scheme 14 shows a general synthesis of intermediate S14-7 where Q is asdefined herein and L_(F) is C₁-C₃ alkylene. Oxidation of intermediateS14-1 (e.g Dess-Martin periodinane) produces ketone S14-2. Treatment ofS14-2 with S14-3 (e.g. R² is —CF₃) in the presence of suitable reagent(such as CsF) provides intermediate S14-4. Deprotection of S14-4 (e.g.TBAF) provides S14-5, which is then added to an isocyanate S14-6 to giveintermediate S14-7.

Scheme 15 shows a general synthesis of an intermediate (±)-S15-3,generated from the Kulinkovich reaction of a Grignard reagent S15-1 andan ester S15-2, according to standard procedures as described inKulinkovich, O. G. and Kananovich, D. G., Eur. J. Org. Chem. 2007, 2007,2121.

Scheme 16 shows a general synthesis of an intermediate S16-4 where Q, M,and T are as defined herein and L_(F) is C₁-C₃ alkylene. In Scheme 16,olefin S16-1 undergoes oxidative cleavage (e.g. OsO₄, NalO₄) to aldehydeS16-2, which is then reduced to alcohol S16-3 (e.g. NaBH₄) and finallyis dehydrated (e.g. Greico elimination) to afford intermediate S16-4.

Scheme 17 shows two general synthetic strategies for producingintermediate S17-3 where J is as defined herein. In Scheme 17, anappropriately protected 4-oxo proline S17-1 is deprotonated andalkylated (e.g. LiHMDS followed by J-LG). A second deprotonation withbase followed by re-protonation at low temperature generatesstereoenriched intermediate S17-2, based on a described protocol(Blanco, M-J. et. al. J. Org. Chem. 1999, 64, 8786). Reduction of theketone in a stereoselective manner (e.g. CBS reduction) provides alcoholS17-3. Where J is methyl, Scheme 17 shows an alternative generalsynthesis wherein intermediate S17-4 is hydrogenated to generate amixture of S17-5 and S17-6. Ketone reduction of S17-5 in astereoselective manner (e.g. CBS reduction) provides intermediate S17-3,where J is methyl.

Scheme 18 shows a general synthesis of intermediates S18-4 and S18-5,wherein an appropriately protected 4-oxo proline S18-1 is hydroxylatedin a stereoselective manner (e.g. MoOPh) to provide intermediate S18-2,which is subsequently reacted with an alkylating agent (e.g.trimethyloxonium tetrafluoroborate) to afford intermediate S18-3.Reduction of the ketone (e.g. BH₃.SMe₂ complex) provides intermediatesS18-4 and S18-5.

Scheme 19 shows a general synthesis of an intermediate S19-7 where Q isas defined herein and L_(F) is C₁-C₃ alkylene. In Scheme 19, an epoxideintermediate S19-1 is converted to the (±)-trans-intermediate S19-3.Activation of the alcohol intermediate (±)-S19-3 (e.g. DSC) producescarbonate (±)-S19-4, which is treated with intermediate S19-5 to affordcarbamate intermediate S19-6. Intermediate S19-6 then undergoes esterhydrolysis (e.g. LiOH when R=methyl or TFA when R=tert-butyl) to provideintermediate S19-7.

Scheme 20 shows a general synthesis of an intermediate S20-3 whereL_(F)-O is F, and U, W, R¹, J, Q, M, T and L are as defied herein. Inscheme 20, intermediate S20-1 first undergoes oxidative cleavage of anolefin (e.g. OsO₄, NaIO₄) and subsequent reduction of the resultantaldehyde (e.g. NaBH₄) to provide intermediate S20-2. Transition metalcatalyzed cross coupling provides intermediate S20-3.

Scheme 21 shows a general synthesis of an intermediate S21-7 where Q andT are as defined herein. In Scheme 21, activation of mono-protected diolS21-1 (e.g. DSC) followed by coupling with amino ester intermediateS21-3 provides carbamate intermediate S21-4. Intermediate S21-4 is thendeprotected to unmask the alcohol functionality (intermediate S21-5)which is then allylated to provide intermediate S21-6. IntermediateS21-6 then undergoes ester hydrolysis (e.g. LiOH when R=methyl or TFAwhen R=tert-butyl) to provide intermediate S21-7.

Scheme 22 shows a general synthesis of an intermediate S22-3 where U, W,R¹, J, and Q are as defied herein. In scheme 22 intermediate S22-1 isglobally deprotected to provide amino acid intermediate S22-2. The acidfunctionality of intermediate S22-2 is then converted to a base-labilecarboxylic acid ester (e.g. methyl ester), intermediate S22-3.

Preparation of Selected Intermediates Preparation of Intermediate A1.

Steps 1-3. Preparation of Intermediate A1: Intermediate A1 was preparedusing the procedure detailed in Example 2.12 of International PatentPublication No. WO 2008/064066 (hereinafter “WO '066”) (p. 75-76)substituting (1R,2S)-methyl1-(tert-butoxycarbonylamino)-2-vinylcyclopropane-carboxylate (preparedaccording to Beaulieu, P. L., et al., J. Org. Chem. 2005, 70, 5869) for(1R,2S)-ethyl1-(tert-butoxycarbonylamino)-2-vinylcyclopropane-carboxylate.

Preparation of Intermediate A2.

Intermediate A2 was prepared similarly to Intermediate A1, substituting1-methylcyclopropane-1-sulfonamide (prepared according to Example 1.2 ofWO '066, p. 47) for cyclopropanesulfonamide.

Preparation of Intermediate A3.

Step 1. Preparation of A3-1: Cyclopropane ester A3-1 was prepared from(1R,2S)-methyl1-(tert-butoxycarbonylamino)-2-vinylcyclopropanecarboxylate (preparedaccording to Beaulieu, P. L., et al., J. Org. Chem. 2005, 70, 5869)using the procedure detailed in Example 26 of International PatentPublication No. WO 2009/005677 (hereinafter “WO '677”) (p. 176).Steps 2-4. Preparation of Intermediate A3: Intermediate A3 was preparedsimilarly to(1R,2S)-1-amino-N-(cyclopropylsulfonyl)-2-vinylcyclopropanecarbox-amidehydrochloride of Example 2.12 of WO '066 (p. 75-76) substituting A3-1for (1R,2S)-ethyl1-(tert-butoxycarbonylamino)-2-vinylcyclopropane-carboxylate.

Preparation of Intermediate A4.

Intermediate A4 was prepared similarly to Intermediate A3, substituting1-methylcyclopropane-1-sulfonamide (prepared according to Example 1.2 ofWO '066, p. 47) for cyclopropanesulfonamide.

Preparation of Intermediate A5.

Steps 1-3. Preparation of Intermediate A5: Intermediate A5 was preparedsimilarly to(1R,2S)-1-amino-N-(cyclopropylsulfonyl)-2-vinylcyclopropane-carboxamidehydrochloride of Example 2.12 of WO '066 (p. 75-76) substituting A5-1(prepared according to Example 104 of WO '677, p. 265) for (1R,2S)-ethyl1-(tert-butoxycarbonylamino)-2-vinylcyclopropanecarboxylate.

Preparation of Intermediate A6.

Intermediate A6 was prepared similarly to Intermediate A5, substituting1-methylcyclopropane-1-sulfonamide (prepared according to Example 1.2 ofWO '066, p. 47) for cyclopropanesulfonamide.

Preparation of Intermediate A7.

Intermediate A7 was prepared according to Example 97.1.6 of U.S. PatentPublication No. 2009/274652 (hereinafter “US '652”), p. 72-73.

Preparation of Intermediate A8.

Steps 1-2. Preparation of Intermediate A8: Intermediate A8 was preparedsimilarly to(1R,2S)-1-amino-N-(cyclopropylsulfonyl)-2-vinylcyclopropane-carboxamidehydrochloride of Example 2.12 of WO '066 (p. 75-76) substituting A8-1(prepared according to the procedure detailed in Example 97.1.4 of US'652, p. 72-3) for(1R,2S)-1-(tert-butoxycarbonylamino)-2-vinylcyclo-propanecarboxylic acidand substituting 1-methylcyclopropane-1-sulfonamide (prepared accordingto Example 1.2 of WO '066, p. 47) for cyclopropanesulfonamide. A8-1 ¹HNMR (400 MHz, CDCl₃) δ 9.22 (br s, 1H), 6.05-5.75 (m, 1H), 5.38 (br s,1H), 2.04 (m, 2H), 1.68 (m, 2H), 1.61 (m, 3H), 1.52 (m, 9H), 1.42 (m,1H), 1.28 (m, 1H), 0.85 (m, 2H).

Preparation of Intermediate A9.

Step 1-2. Preparation of Intermediate A9: Intermediate A9 was preparedsimilarly to(1R,2S)-1-amino-N-(cyclopropylsulfonyl)-2-vinylcyclopropane-carboxamidehydrochloride of Example 2.12 of WO '066 (p. 75-76) substituting A9-1(prepared according to Example 1, Steps 1L-1O of International PatentPublication No. WO 2009/134987, p. 75-77) for(1R,2S)-1-(tert-butoxycarbonylamino)-2-vinylcyclopropanecarboxylic acid.

Preparation of Intermediate A10.

Intermediate A10 was prepared similarly to Intermediate A9, substituting1-methylcyclopropane-1-sulfonamide (prepared according to Example 1.2 ofWO '066, p. 47) for cyclopropanesulfonamide.

Preparation of Intermediate A11.

Step 1. Preparation of A11-1: To a solution of NaOH (46.2 g, 50% w/w inwater) at rt was added BnEt₃NCl (10.5 g, 46 mmol), di-tert-butylmalonate (10 g, 46 mmol) and 1,2-dibromopropane (14 g, 69.3 mmol). Themixture was stirred at rt overnight and was extracted with DCM (3×100mL). The organic layers were washed with water (80 mL) and brine (50mL), dried over anhydrous Na₂SO₄. Concentration in vacuo produced A11-1that was used subsequently without further purification. ¹H NMR (400MHz, CDCl₃) δ 1.83-1.62 (m, 1H); 1.42 (s, 9H); 1.40 (s, 9H); 1.24-1.05(m, 2H); 1.03-1.02 (d, 3H).Step 2. Preparation of A11-2: To a mixture of t-BuOK (175 g, 1.56 mol)in ether (1.2 L) at 0° C. was added water (3.4 mL) followed by additionof diester A11-1 (91 g, 0.35 mol). The mixture was stirred at rt forthree days, then quenched with ice-water. The aqueous layer wasextracted with ether (2×400 mL), acidified with critic acid, and thenextracted with EA (3×400 mL). The combined ethyl acetate extracts werewashed with water (2×100 mL), brine (200 mL), dried over anhydrousNa₂SO₄, and concentrated in vacuo to produce A11-2 that was usedsubsequently without further purification. ¹H NMR (400 MHz, DMSO-d₆) δ12.60 (s, 1H); 1.70-1.64 (s, 1H); 1.37 (s, 9H); 1.19-1.13 (m, 1H);1.03-1.00 (m, 4H).Step 3. Preparation of A11-3: To a mixture A11-2 (33.5 g, 0.17 mol) andtriethylamine (70 mL) in THF (200 mL) at 0° C. was added ethylchloroformate (22 mL). The mixture was stirred at 0° C. for 1 h. To themixture at 0° C. was added sodium azide (54 g, 0.83 mol, 4.9 eq) inwater (100 mL), the mixture was stirred for 40 min. The mixture wasextracted with EA (2×400 mL), washed with water (100 mL), brine (100mL), dried over anhydrous Na₂SO₄ and concentrated in vacuo to produce aresidue that was taken up in toluene (100 mL) and treated with benzylalcohol (50 mL). The mixture was then heated at 70° C. for 2 h, cooledto rt, adjusted to pH 8 with sodium bicarbonate, and then extracted withether (3×200 mL). The aqueous layer was then adjusted to pH 5 with 1 NHCl and extracted with EA (2×300 mL). The combined ethyl acetateextracts were washed with water (100 mL), brine (80 mL), dried overanhydrous Na₂SO₄, and concentrated in vacuo to give CBZ protected amineA11-3 (16 g) that is used subsequently without further purification. ¹HNMR (400 MHz, DMSO-d₆) δ 7.85 (s, 1H); 7.28-7.15 (m, 5H); 4.97-5.03 (m,2H); 1.33 (s, 9H); 1.33-1.17 (m, 2H); 1.10 (d, J=6.8 Hz, 3H); 0.90-1.00(m, 1H).Steps 4 and 5. Preparation of A11-4: To a solution of Cbz protectedamine A11-3 (16 g, 52 mmol) in DCM (250 mL) was added dropwise TFA (250mL, 3.24 mol) at rt and the mixture stirred at rt overnight. The mixturewas concentrated in vacuo, adjusted to pH 8-9 using aqueous sodiumcarbonate and washed with ether (3×80 mL). The aqueous phase was thenadjusted to pH 5-6 using 1 N HCl and extracted with EA (2×300 mL). Thecombined ethyl acetate phases were washed with water (80 mL), brine (80mL), dried over anhydrous Na₂SO₄ and concentrated to give 13 g as aslightly yellow oil that was used in the next step without furtherpurification. This material (8.0 g, 32 mmol) was taken up in methanol(200 mL), treated with thionyl chloride (15 mL) at 0° C., then stirredat rt overnight. The resulting mixture was concentrated in vacuo andpurified by flash chromatography on silica (eluent PE/EA 10:1-5:1) togive methyl ester A11-4 (6 g). ¹H NMR (400 MHz, DMSO-d₆) δ 7.97 (s, 1H);7.37-7.26 (m, 5H); 4.99 (s, 2H); 3.61 (s, 3H); 1.48-1.45 (m, 1H);1.17-1.08 (m, 2H); 1.06-1.04 (d, 3H).Step 6. Preparation of A11-5: Cbz carboxamide A11-4 (36 g, 0.15 mol),Boc₂O (40 g, 0.18 mol), and Pd/C (3.6 g, 10% w/w) were combined inmethanol under H₂ and stirred at 32° C. overnight. The reaction mixturewas filtered to remove the catalyst, additional Boc₂O (40 g, 0.18 mol)and Pd/C (3.6 g, 10% w/w) were added and the reaction placed under a H₂atmosphere with stirring at rt for a weekend. The reaction mixture wasfiltered to remove the catalyst, concentrated in vacuo and purified byflash chromatography on silica (eluent PE/EA 20:1-10:1) to produce Bocprotected amine A11-5. ¹H NMR (400 MHz, DMSO-d₆) δ 7.48 (s, 1H), 3.59(s, 3H), 1.43-1.41 (m, 1H), 1.34 (s, 9H), 1.21-1.18 (m, 1H), 1.07-1.01(m, 4H).Step 7. Preparation of A11-6: To a solution of NaH₂PO₄ (1.9 g) in water(160 mL) at 40° C. was added Alcalase (2.4 U/g, 16 mL). The mixture wasadjusted with 50% aqueous sodium hydroxide to pH 8. A11-5 (2.80 g) inDMSO (32 mL) was added to the buffer dropwise over 30 min. The mixturewas stirred at 40° C. and maintained at pH 8 with addition of 50% NaOHfor 19 h. The mixture was cooled to rt, with ether (3×100 mL) and theorganic phase washed with sat. NaHCO₃ (2×40 mL), water (2×40 mL), brine(40 mL), dried over anhydrous Na₂SO₄, filtered and concentrated in vacuoto produce A11-6. ¹H NMR (300 MHz, DMSO-d₆) δ 5.18 (br s, 1H); 3.71 (s,3H); 1.43-1.18 (m, 2H); 1.34 (s, 9H); 1.07-1.01 (m, 4H). Analysis of theproduct using chromegaChiral CC3 column (0.46 cm I.D.×25 cm L, 3 μLinjection, 80/20 hexane/IPA, 1 mL/min, 34° C., 220 nM UV detection)determined the enantiomeric excess was 99.4% (desired RT=5.238 min,undesired RT=6.745 min).Steps 8 and 9. Preparation of A11-7: Solid LiOH*H₂O (19.1 g, 455 mmol)is taken up in 50 mL MeOH/50 mL water at rt. Once all LiOH hasdissolved, methyl ester A11-6 (10.4 g, 45.5 mmol) is taken up in 100 mLTHF added to reaction mixture and stirred vigorously overnight. Theresulting solution is diluted with water (150 mL), adjusted to pH 3 with12 M HCl and extracted with EtOAc. The combined organic layers arewashed with brine, dried over anhydrous MgSO₄ and concentrated in vacuoto produce a fine white powder (9.2 g). This material (1.5 g, 7 mmol) istaken up in THF (30 mL) and treated with CDI (1.47 g, 9.1 mmol). Theresulting solution was heated to 65° C. for 2 h, cooled to rt andtreated with DBU (2.1 mL, 13.9 mmol) and1-methylcyclopropane-1-sulfonamide (1.4 g, 10.5 mmol). The resultingsolution is stirred at rt overnight. Addition of 1 M HCl is used toadjust the pH ˜1 prior to removing the majority of THF in vacuo. Theresulting slurry is extracted with EtOAc and the combined organicswashed with brine, dried over anhydrous MgSO₄ and concentrated in vacuoto produce 2.29 g of acyl sulfonamide A11-7. LCMS-ESI (m/z): [M+Na]⁺calcd for C₁₄H₂₄N₂NaO₅S: 355.41. found: 355.84.Step 10. Preparation of Intermediate A11. Acyl sulfonamide A11-7 (0.25g, 0.75 mmol) in dioxane (1 mL) is treated with HCl (4 M in dioxane, 2.8mL, 11.2 mmol) at rt. After 4 h, the reaction is concentrated in vacuoto produce 0.20 g of Intermediate A-11 that is used subsequently withoutadditional purification. ¹H NMR (400 MHz, CD₃OD) δ 1.87-1.84 (m, 0.5;H); 1.77-1.65 (m, 1.5H); 1.58-1.46 (m, 2H); 1.54 (d, J=8 Hz, 3H);1.34-1.26 (m, 3+1H); 1.02-0.92 (m, 1H); 0.83-0.77 (m, 1H).

Preparation of Intermediate A12.

Step 1. Preparation of A12-1: A vessel containing a solution ofcarboxylic acid A9-1 (1 g, 4 mmol) in THF (15 mL) was treated with CDI(0.84 g, 5.2 mmol), sealed and heated to 75° C. for 2 h. The clear tancolored solution is divided in half and used subsequently withoutfurther purification for the remainder of Step 1 in the preparation ofIntermediate A12 as well as the preparation of Intermediate A13 asdetailed below. This solution is treated with1-fluorocyclopropane-1-sulfonamide (0.42 g, 3 mmol; prepared accordingto Steps 1, 4, and 9 of Example 7 of International Patent PublicationNo. WO 2009/14730, p. 107-110) and DBU (0.6 mL, 4 mmol) and allowed tostir overnight at rt. The solution was acidified to pH ˜1 with 1 M HCland concentrated in vacuo to remove the majority of THF. The aqueouslayer was extracted with EtOAc and the combined organics washed withbrine, dried over anhydrous MgSO₄ and concentrated in vacuo to drynessto afford 0.73 g of the A12-1 that was used without furtherpurification.Step 2. Preparation of Intermediate A12: Acyl sulfonamide A12-1 (0.25 g,0.67 mmol) was taken up in 1 mL dioxane and treated with HCl (4 M indioxane, 2.5 mL, 11 mmol). The reaction was stirred at rt for 2 h andconcentrated in vacuo to dryness to afford a quantitative yield ofIntermediate A12. ¹H NMR (400 MHz, CD₃OD) δ 6.04 (td, J_(H-F)=55.6 Hz,J=5.2 Hz, 1H); 2.25-2.14 (m, 1H); 1.78-1.62 (m, 2H); 1.52-1.38 (m, 4H).

Preparation of Intermediate A13.

Intermediate A13 was prepared similarly to Intermediate A12,substituting 1-chlorocyclopropane-1-sulfonamide (prepared according toLi, J, et al. Synlett, 2006, 5, pp. 725-728) for1-chlorocyclopropane-1-sulfonamide in Step 1. ¹H NMR (400 MHz, CD₃OD) δ6.03 (td, J_(H-F)=54.8 Hz, J=6 Hz, 1H); 2.32-2.18 (m, 1H); 2.06-1.92 (m,2H); 1.80-1.68 (m, 2+1H); 1.56-1.44 (m, 1H); 1.44-1.37 (m, 1H).

Preparation of Intermediate B1.

Steps 1 and 2. Preparation of Intermediate B1: Enaminone B1-1 (4.0 g,11.8 mmol, prepared according to Camplo, M., et al. Tetrahedron 2005,61, 3725) was dissolved in acetone (120 mL) and the reaction vessel waspurged with Ar. Pd/C (10 wt. % Pd, 820 mg) was added in a single portionand the reaction vessel was purged twice with H₂. The reaction wasstirred under 1 atm H₂ at rt for 15 h and was then filtered through apad of Celite with acetone. The filtrate was concentrated and filteredthrough a plug of silica gel with 30% EtOAc in hexanes to afford a ˜2:1mixture of ketones B1-2 and B1-3 (3.48 g) as a white solid. This mixture(3.37 g, 11.3 mmol) was dissolved in THF (100 mL) under Ar. A 1 Msolution of (R)-(+)-2-methyl-CBS-oxazaborolidine in toluene (11.3 mL,11.3 mmol) was added in a single portion and the resulting solution wascooled to −78° C. A 1 M solution of BH₃.SMe₂ in CH₂Cl₂ (11.3 mL) wasthen added dropwise over 5 min. The resulting solution was stirred for20 min and was removed from the cold bath. After an additional 15 min,the reaction was placed in a water bath at ambient temperature. After anadditional 7 min, the reaction was quenched by dropwise addition of MeOH(20 mL). After stirring an additional 2.5 h, the reaction mixture wasconcentrated, dissolved in EtOAc (300 mL), and washed with 0.2 M HCl(200 mL). The phases were separated, and the aqueous phase was extractedwith EtOAc (100 mL). The combined organic phase was filtered to removesolids, dried over Na₂SO₄, filtered, and concentrated. The crude residuewas dissolved in CH₂Cl₂ and was concentrated onto 20 g silica gel.Purification by silica gel chromatography (25 to 40% EtOAc in hexanes)provided partial separation of Intermediate B1 from other diastereomericproducts. Mixed fractions were pooled and concentrated onto 9 g silicagel. Purification by silica gel chromatography provided Intermediate B1contaminated with minor diastereomeric components as a white solid (1.96g). ¹H NMR (400 MHz, CDCl₃, rotamers observed) δ 4.25-4.15 (m, 1H),4.13-4.04 (m, 1H), 3.91-3.79 (m, 1H), 3.28-3.09 (m, 1H), 2.41-2.23 (m,1H), 2.04 (bs, 1H), 1.51-1.39 (m, 18H), 1.09-1.01 (m, 3H).

Preparation of Intermediate B2.

Steps 1 and 2. Preparation of B2-1: trans-3-Hydroxy-L-proline (571 mg,4.35 mmol, Chem-Impex International, Inc.) was suspended in MeOH andcooled to 0° C. Thionyl chloride (1.6 mL, 22 mmol) was added over 5 minand the solution was warmed to rt. After stirring for 24 h, the reactionmixture was concentrated under reduced pressure to afford the methylester, which was carried on without further purification. The crudeester was suspended in DCM (22 mL) and treated with TEA (1.3 mL, 9.57mmol). The stirred mixture was cooled to 0° C. and trityl chloride (1.21g, 4.35 mmol) was added. The reaction mixture was allowed to graduallycome to rt o/n, and then poured into saturated aqueous NaHCO₃. Theaqueous layer was extracted three times with DCM. The combined organicswere dried over Na₂SO₄, filtered and concentrated under reducedpressure. The crude residue was purified by silica gel chromatography(25% to 50% EtOAc/Hex to afford alcohol B2-1 (1.27 g).Step 3. Preparation of B2-2: Alcohol B2-1 (1.23 g, 3.18 mmol) and 2 g 4Å MS were suspended in DCM (16 mL) and treated with NMO (560 mg, 4.78mmol) and TPAP (76 mg, 0.218 mmol). After stirring for 30 min, themixture was filtered over a short pad of silica and eluted off with 50%EtOAc/Hex. The filtrate was concentrated and the crude residue waspurified by silica gel chromatography (10% to 30% EtOAc/Hex to affordketone B2-2 (0.99 g).Step 4. Preparation of B2-3: LiHMDS (1.0 M in THF, 5.8 mL, 5.8 mmol) wasadded to THF (22 mL) and the stirred solution was cooled to −78° C. A rtsolution of ketone B2-2 (2.14 g, 5.55 mmol) in THF (6 mL) was addeddropwise by cannula over 5 min. The flask that had contained B2-2 wasthen rinsed with THF (4 mL) and the rinsing was added dropwise bycannula to the reaction mixture. After 35 min,N-(5-chloro-2-pyridyl)bis(trifluoromethanesulfonimide) (2.40 g, 6.11mmol) in THF (6 mL) was added to the reaction mixture dropwise bysyringe over 5 min. After another 1 h, the reaction mixture was warmedto rt. Following an additional 30 min, the reaction was quenched byaddition of 20 mL H₂O and diluted with Et₂O. The organic solution waswashed with 10% NaOH and dried over K₂CO₃, filtered and concentratedunder reduced pressure. The crude residue was loaded onto a silicacolumn that had been pre-equilibrated with 1% TEA/Hex. The material waspurified by silica gel chromatography (0% to 15% EtOAc/Hex doped with 1%TEA) to afford enol triflate B2-3 (1.89 g). Step 5. Preparation of B2-4:Enol triflate B2-3 (957 mg, 1.85 mmol) was dissolved in THF (9 mL) andtreated with Pd(PPh₃)₄(107 mg, 0.0925 mmol) and dimethyl zinc (2.0 M inPhMe, 1.9 mL, 3.7 mmol). The reaction mixture was stirred at rt for 5 h,then more dimethyl zinc (2.0 M in PhMe, 1.9 mL, 3.7 mmol) was added andthe reaction was heated to 50° C. for 15 min. After cooling to rt, themixture was diluted with Et₂O. The organic solution was washed with 10%NaOH twice, then dried over MgSO₄, filtered and concentrated underreduced pressure. The crude B2-4 residue was carried on without furtherpurification.Steps 6 and 7. Preparation of B2-5: Compound B2-4 (1.85 mmoltheoretical) was dissolved in 1:1 MeOH/DCM (20 mL) and treated with HCl(4.0 M in dioxane, 2 mL, 8.0 mmol). After stirring for 2 h at rt, thereaction mixture was concentrated and the crude material was carried onwithout further purification. The crude product amine hydrochloride wastreated with Boc₂O (2.02 g, 9.25 mmol), DCM (18 mL), MeOH (1.8 mL) andTEA (0.52 mL, 3.7 mmol). After stirring for 2 h at rt, the reactionmixture was diluted with EtOAc and washed with 10% HCl, saturatedaqueous NaHCO₃ and brine. The organic solution was dried over MgSO₄,filtered and concentrated under reduced pressure. The residue waspurified by silica gel chromatography (15% to 40% EtOAc/Hex) to affordcarbamate B2-5 (331 mg). LCMS-ESI⁺ (m/z): [M+H]⁺ calcd for C₁₂H₂₀NO₄:242.14. found: 243.26.Step 8. Preparation of Intermediate B2: Carbamate B2-5 (345 mg, 1.43mmol) was dissolved in THF (7 mL) and cooled to 0° C. BH₃.SMe₂ complex(2.0 M in THF, 0.79 mL, 1.58 mmol) was added dropwise and the reactionmixture was allowed to come to rt gradually. After 15 h, the reactionwas quenched by dropwise addition of H₂O (added until bubbling ceased),then cooled to 0° C. Hydrogen peroxide (30% w/w in H₂O, 0.73 mL, 7.2mmol) and NaOH (2.0 M in H₂O, 0.86 mL, 1.72 mmol) were added in quicksuccession and the stirred mixture was heated to 50° C. for 35 min. Themixture was then diluted with Et₂O and washed successively with H₂O,saturated aqueous NaHCO₃ and brine, then dried over MgSO₄, filtered andconcentrated under reduced pressure. Intermediate B2 was used insubsequent reactions without further purification. LCMS-ESI⁺ (m/z):[M+H]⁺ calcd for C₁₂H₂₂NO₅: 260.15. found: 259.99.

Preparation of Intermediate B3.

Step 1. Preparation of B3-1: Enol triflate B2-3 (91 mg, 0.176 mmol) wasdissolved in THF (1.7 mL) and treated with cyclopropyl zinc bromide (0.5M in THF, 1.7 mL, 0.85 mmol) and Pd(PPh₃)₄ (20 mg, 0.018 mmol). Thestirred reaction mixture was heated to 50° C. for 2 h then cooled to rtand diluted with EtOAc. The organic solution was washed successivelywith saturated aqueous NaHCO₃ and brine, then dried over MgSO₄, filteredand concentrated under reduced pressure. The crude residue was purifiedby silica gel chromatography (0% to 20% EtOAc/Hex) to affordcyclopropane B3-1 (43 mg). LCMS-ESI⁺ (m/z): [M−Tr+H]⁺ calcd forC₉H₁₄NO₂: 168.10. found: 168.04.Steps 2 and 3. Preparation of B3-2: Vinyl cyclopropane B3-1 (43 mg, 0.11mmol) was dissolved in 1:1 MeOH/DCM (10 mL) and treated with HCl (4.0 Min dioxane, 1 mL, 4.0 mmol). After stirring for 1.5 h at rt, thereaction mixture was concentrated and the crude material was carried onwithout further purification. The crude product of step 2 was treatedwith Boc₂O (229 mg, 1.05 mmol), DMAP (13 mg, 0.105 mmol), DCM (5 mL) andTEA (0.293 mL, 2.10 mmol). After stirring for 5 h at rt, the reactionmixture was diluted with EtOAc and washed with 10% HCl, saturatedaqueous NaHCO₃ twice and brine. The organic solution was dried overMgSO₄, filtered and concentrated under reduced pressure. The residue waspurified by silica gel chromatography (10% to 30% EtOAc/Hex) to affordcarbamate B3-2 (20 mg). LCMS-ESI⁺ (m/z): [M−(t-Bu)+H]⁺ calcd forC₁₀H₁₄NO₄: 212.09. found: 211.91.Step 4. Preparation of Intermediate B3: Carbamate B3-2 (152 mg, 0.569mmol) was dissolved in THF (5.7 mL) and cooled to 0° C. BH₃*SMe₂ complex(2.0 M in THF, 0.31 mL, 0.63 mmol) was added dropwise and the reactionmixture was allowed to come to rt gradually. After 20 h, the reactionwas quenched by dropwise addition of H₂O (added until bubbling ceased),then cooled to 0° C. Hydrogen peroxide (30% w/w in H₂O, 0.29 mL, 2.85mmol) and NaOH (2.0 M in H₂O, 0.43 mL, 0.86 mmol) were added in quicksuccession and the stirred mixture was heated to 50° C. for 30 min. Themixture was then diluted with Et₂O and washed successively with H₂O,saturated aqueous NaHCO₃ and brine, then dried over MgSO₄, filtered andconcentrated under reduced pressure. Intermediate B3 was carried onwithout further purification. LCMS-ESI⁺ (m/z): [M-(t-Bu)+H]⁺ calcd forC₁₀H₁₆NO₅: 230.10. found: 230.03.

Preparation of Intermediate B4.

Intermediate B4 ((2S,3S,4R)-di-tert-butyl3-ethyl-4-hydroxypyrrolidine-1,2-dicarboxylate) was prepared accordingto Camplo, M., et al. Tetrahedron 2005, 61, 3725.

Preparation of Intermediate B5.

Step 1. Preparation of enone B5-2: To a solution of B1-1 intetrahydrofuran (7.35 mL) was added ethylmagnesium bromide (3 M indiethyl ether, 1.47 mL 4.41 mmol) via syringe at −78° C. under an argonatmosphere. After 2.5 h, the reaction mixture was allowed to warm to rtover 30 min at which point the reaction mixture was diluted withsaturated aqueous ammonium chloride solution (20 mL). The resultingmixture was extracted with ethyl acetate (20 mL twice), and the combinedorganic extracts were dried over anhydrous sodium sulfate and wereconcentrated in vacuo. The crude residue was purified by silica gelchromatography (0-100% ethyl acetate/hexanes gradient) to affordintermediate B5-1 (308.8 mg) as a colorless oil. LCMS-ESI (m/z): [M+H]⁺calcd for C₁₇H₂₈NO₅: 326.2. found: 326.2.Step 2. Preparation of B5-2: To a solution of enone B5-1 (308 mg, 0.95mmol) in methanol (4.7 mL) was added cerium(III) chloride heptahydrate(566 mg, 1.52 mmol) at rt under an argon atmosphere. The resultingmixture was cooled to −78° C., and sodium borohydride (57.7 mg, 1.52mmol) was added as a solid. After 1 h, the reaction mixture was warmedto 0° C. and saturated aqueous ammonium chloride (20 mL) was added. Theresulting mixture was extracted with ethyl acetate (20 mL twice), andthe combined organic extracts were dried over anhydrous sodium sulfateand were concentrated in vacuo to afford allylic alcohol B5-2 (319.3 mg)as a colorless oil, which was used directly in the next step withoutpurification. LCMS-ESI (m/z): [M+H]⁺ calcd for C₁₇H₂₉NO₅: 328.2. found:328.2.Step 3. Preparation of Intermediate B5: To a solution of alcohol B5-2(319 mg, 0.98 mmol) in ethanol (4.9 mL) was added Pd/C (10%, 103.9 mg,0.097 mmol) at rt under an argon atmosphere. The atmosphere was replacedwith hydrogen and the reaction mixture was stirred vigorously at rt.After 16 h, the reaction mixture was diluted with ethyl acetate (25 mL)and was filtered through a pad of Celite with ethyl acetate washings (10mL three times). The filtrate was concentrated in vacuo to affordIntermediate B5 (188 mg), which was used directly in the next stepwithout purification. LCMS-ESI (m/z): [M+H]⁺ calcd for C₁₇H₃₂NO₅: 330.2.found: 330.3.

Preparation of Intermediate B6.

Step 1. Preparation of B6-1: A solution of isopropylmagnesium bromide(2.9 M in MeTHF, 3.2 mL, 9.3 mmol) was added dropwise to a cooledsolution of B1-1 (1.02 g, 3.00 mmol) in 60 mL of ether at −78° C. underargon. Reaction mixture was warmed to room temperature and stirred for 3hours. Reaction mixture was quenched with sat. aqueous NH₄Cl andextracted three times with ether. Combined organics were washed withsat. aqueous NaHCO₃ and brine, dried (MgSO₄), filtered, and concentratedunder reduced pressure. The resulting residue was purified by silica gelchromatography (0-30% ethyl acetate in hexanes) to yield B6-1 (743 mg)as a light yellow oil. ¹H NMR (400 MHz, CDCl₃): δ 6.60 (dd, J=10.8, 2.4Hz, 1H), 5.14 and 5.06 (rotamers, d, J=2.4 Hz, 1H), 3.96 (m, 2H), 2.91(m, 1H), 1.46 (s, 9H), 1.27 (s, 9H), 1.04 (d, J=8.8 Hz, 6H).Step 2. Preparation of B6-2 and B6-3: CeCl₃.7H₂O (1.32 g, 3.50 mmol) wasadded to a solution of B6-1 (740 mg, 2.18 mmol) in 47 mL of methanol atroom temperature under argon. After cooling to −78° C., sodiumborohydride (127 mg, 3.34 mmol) was added slowly portionwise. After twohours, reaction mixture was warmed to 0° C. After fifteen minutes,reaction mixture was quenched with sat. aqueous NH₄Cl and extractedthree times with ethyl acetate. Combined organics were washed withbrine, dried (MgSO₄), filtered, and concentrated under reduced pressureto yield a ˜3:1 mixture of B6-2 (major) and B6-3 (minor) as a colorlessfilm (738 mg), which was used in the next step without furtherpurification. ¹H NMR (400 MHz, CDCl₃): δ 5.68-5.48 (m, 1H), 4.90-4.31(m, 2H), 4.05-3.15 (m, 2H), 2.90-2.61 (m, 1H), 1.50-1.39 (br s, 18H),1.02 (d, J=9.2 Hz, 6H).Step 3. Preparation of Intermediate B6: The ˜3:1 mixture of B6-2 andB6-3 (341 mg, 1.00 mmol) was dissolved in 28 mL of ethyl acetate.Palladium on carbon (10 wt %, 109 mg, 0.11 mmol) was then added andmixture was hydrogenated under an atmosphere of hydrogen for nineteenhours. Mixture was then filtered over Celite, washing with ethylacetate, and filtrate was concentrated under reduced pressure. Theresulting residue was purified by silica gel chromatography (0-50% ethylacetate in hexanes) to yield Intermediate B6 (141 mg) as a colorlessoil. ¹H NMR (400 MHz, CDCl₃): δ 4.31-4.17 (m, 2H), 3.97-3.85 (m, 1H),3.21-3.07 (m, 1H), 2.35-2.18 (m, 1H), 1.92-1.78 (m, 1H), 1.47-1.37 (m,18H), 1.35-1.19 (m, 2H), 0.94 (d, J=8.8 Hz, 6H).

Preparation of Intermediate B7.

Step 1. Preparation of B7-2: To a solution of alcohol B7-1 (500 mg, 1.33mmol; prepared according to Barreling, P., et al. Tetrahedron 1995, 51,4195) in DCM (6.65 mL) was added Dess-Martin periodinane (564 mg, 1.33mmol) at rt under an argon atmosphere. After 2 h, the reaction mixturewas purified directly by silica gel chromatography (0-100% ethylacetate/hexanes gradient) to afford ketone B7-2 (431 mg) as a colorlessoil. LCMS-ESI (m/z): [M+H]⁺ calcd for C₂₁H₃₀NO₅: 376.2. found: 376.2.Step 2. Preparation of Intermediate B7: To a solution of intermediateB7-2 (410 mg, 1.09 mmol) and (R)-(+)-2-methyl-CBS-oxazaborolidine(Aldrich, 1M in toluene, 1.09 mL, 1.09 mmol) in THF (5.45 mL) was addedBH₃.THF (1M in toluene, 2.18 mL, 2.18 mmol) at −78° C. under an argonatmosphere. After 1 h, the reaction mixture was quenched with saturatedaqueous ammonium chloride solution (15 mL) and the resulting mixture wasallowed to warm to rt. The phases where separated and the aqueous phasewas extracted twice (20 mL) with DCM. The combined organic layers weredried over anhydrous sodium sulfate, and were concentrated in vacuo. Thecrude residue was purified by silica gel chromatography (0-100% ethylacetate/hexanes gradient) to afford Intermediate B7 (390.9 mg, 4:1diastereomeric mixture) as a colorless oil. LCMS-ESI⁺ (m/z): [M+H]⁺calcd for C₂₁H₃₂NO₅: 378.2. found: 378.5.

Preparation of Intermediate B8.

Step 1. Preparation of B8-1. n-BuLi (0.44 mL, 1.1 mmol, 2.5M in hexane)was added to a cold (−78° C.) solution of (S)-methyl4-oxo-1-(9-phenyl-9H-fluoren-9-yl)pyrrolidine-2-carboxylate (383 mg, 1mmol, prepared as described in Sardina, F. J., Blanco, M.-J. J. Org.Chem. 1996, 61, 4748) in THF/HMPA (3.8 mL/0.4 mL). The resultingsolution was stirred at −78° C. to −50° C. for 1.5 h, and thenbromoacetonitrile (0.2 mL, 3 mmol) was added. The reaction mixture wasstirred while the temperature was allowed to reach −10° C. (4 h). To thereaction mixture was charged with saturated aqueous NH₄Cl (1 mL) andEtOAc (15 mL). The organic layer was separated, and the aqueous layerwas extracted with EtOAc (10 mL). Both organic layers were combined,washed with H₂O and brine, and dried over Na₂SO₄. The organic layer wasconcentrated and purified via silica gel chromatography to afforddiastereomeric mixture B8-1 (170 mg) as colorless oil.Step 2. Preparation of B8-2. KHMDS (0.4 mL, 0.4 mmol, 1M in THF) wasadded to a cold (−78° C.) solution of B8-1 (140 mg, 0.33 mmol) inTHF/DMPU (1.5 mL/0.75 mL). The resulting solution was stirred at −78° C.for 1.5 h. Then HOAc (0.1 mL) was added. To the reaction mixture wascharged with saturated aqueous NH₄Cl (1 mL) and EtOAc (15 mL). Theorganic layer was separated, and the aqueous layer was extracted withEtOAc (10 mL). Both organic layers were combined, washed with H₂O andbrine, and dried over Na₂SO₄. The organic layer was concentrated andpurified via silica gel chromatography to afford ketone B8-2 (120 mg) ascolorless oil.Step 3. Preparation of Intermediate B8. To an oven-dried,nitrogen-flushed flask was added BH₃.THF (0.28 mL, 0.28 mmol,) followedby (R)-(+)-2-methyl-CBS-oxazaborolidine (0.012 mL, 0.03 mmol, 1.0 M intoluene). A solution of B8-2 (120 mg, 0.28 mmol) in THF (0.5 mL) wasadded dropwise. The reaction mixture was stirred at rt for 60 min, andthen quenched by addition of 1.0 M aqueous HCl (0.2 mL). EtOAc (20 mL)was added and organic phase washed with sat. aqueous NaHCO₃ and brine,and dried over Na₂SO₄. The organic layer was concentrated and purifiedvia silica gel chromatography to afford Intermediate B8 (100 mg) ascolorless oil. LCMS-ESI (m/z): [M]⁺ calcd for C₂₇H₂₄N₂O₃: 424.49. found:424.77.

Preparation of Intermediate C1.

Methyl 3-methyl-N-(oxomethylene)-L-valinate (Intermediate C1) wasprepared according to Step 3 of Intermediate B1 of International PatentPublication No. WO 2010/11566 (hereinafter “WO'566”), p 14.

Preparation of Intermediate C2.

Intermediate C2 (tert-butyl 3-methyl-N-(oxomethylene)-L-valinate) wasprepared in a similar fashion to Intermediate C1, substitutingtert-butyl 3-methyl-L-valinate (Bachem AG) for methyl3-methyl-L-valinate in Step 3 of intermediate B1 of WO'566, p 14.

Preparation of Intermediate D1.

Steps 1 and 2. Preparation of trans-cyclopropanol mixture D1-2 and D1-3:THF (1000 mL) was introduced in a three neck round bottomed flaskcontaining Mg (32.2 g, 1.34 mol). A solution of 7-bromohept-1-ene (216g, 1.22 mol) in THF (600 mL) was introduced to an addition funnel. Onecrystal of iodine and 20 mL of 7-bromohept-1-ene solution were added tothe reaction. The solution was heated to reflux, and the remainder ofthe 7-bromohept-1-ene solution was added drop wise. After the additionwas complete, the mixture was refluxed for an additional 2 h thenallowed to cool to rt to produce a solution of Grignard reagent D1-1,which was then added dropwise to a solution of ethyl formate (30 g, 0.41mol) and Ti(Oi-Pr)₄ (115.2 g, 0.41 mol) in THF (1200 mL) at rt. Afterstirring overnight, the mixture was poured into 1600 mL of 10% aqueousH₂SO₄ and extracted with MTBE (1500 mL three times). The combinedorganic layers were washed with brine, dried over MgSO₄, filtered andconcentrated in vacuo. The residue was purified by silica gelchromatography to afford 31.0 g of a mixture of trans-cyclopropylalcohols D1-2 and D1-3 as a yellow oil. ¹H NMR: (400 MHz, CDCl₃): δ5.77-5.70 (m, 1H), 4.96-4.86 (m, 2H), 3.15-3.12 (m, 1H), 2.03-1.98 (m,2H), 1.75 (br s, 1H), 1.45-1.37 (m, 2H), 1.20-1.15 (m, 1H), 1.06-1.01(m, 1H), 0.89-0.82 (m, 1H), 0.63-0.59 (m, 1H), 0.24 (q, J=6.0 Hz, 1H).Step 3. Preparation of cyclopropyl acetate mixture D1-4 and D1-5: To a1000 mL round bottom flask was added trans-cyclopropyl alcohol mixtureD1-2 and D1-3 (60.3 g, 0.48 mol), 700 mL of DCM and TEA (62.9 g, 0.62mol) prior to cooling the solution in an acetone/ice bath to an internaltemp of <5° C. Acetyl chloride (41.3 g, 0.53 mol) was added dropwise tothe solution over a 30 min period while maintaining an internal temp<10°C. The resulting slurry was then warmed to rt and stirred for 2 h. Thereaction mixture was diluted with 350 mL of water. The biphasic mixturewas transferred to a separatory funnel and the aqueous layer removed.The organic layer was washed with 480 mL of 2 N aqueous HCl and thenwith 500 mL of sat. aqueous NaHCO₃ prior to drying over MgSO₄. Thesolvent was removed in vacuo. The residue was purified by silica gelchromatography to afford a mixture D1-4 and D1-5 (56.3 g) as a yellowoil. TLC Information (PE/EtOAc=5/1) R_(f) (starting material)=0.4; R_(f)(product)=0.8.Step 4. Preparation of D1-3: To a 1000 mL round-bottom flask was added asolution of mixture D1-4 and D1-5 (39 g, 0.23 mol) in 680 mL of MTBEsaturated with aqueous 0.1 M pH 7 phosphate buffer. The flask was placedin an ice bath to maintain an internal temperature of approximately 10°C. throughout the hydrolysis reaction which was initiated by theaddition of 3.0 g of Novozyme 435. The reaction was aged at 10° C. forapproximately 6 h until conversion had reached about 40%. The reactionmixture was filtered, and the solid immobilized enzyme was washed threetimes with 200 mL of MTBE. The resulting MTBE solution was concentratedin vacuo. The residue was purified by silica gel chromatography toafford D1-3 (11.3 g) as a yellow oil. ¹H NMR: (400 MHz, CDCl₃) δ5.80-5.75 (m, 1H), 5.02-4.91 (m, 2H), 3.20-3.17 (m, 1H), 2.09-2.03 (m,3H), 1.50-1.43 (m, 2H), 1.26-1.22 (m, 1H), 1.17-1.08 (m, 1H), 1.07-0.89(m, 1H), 0.70-0.65 (m, 1H), 0.32-0.27 (m, 1H).Step 5. Preparation of D1-6: Cyclopropanol D1-3 (17.7 g, 0.140 mol) wasdissolved in 300 mL of MeCN at 0° C. To the solution was added DSC (72.0g, 0.280 mol) and TEA (42.42 g, 0.420 mol). The reaction mixture waswarmed to 40° C. and stirred overnight and then concentrated in vacuo.The residue was purified by silica gel chromatography to afford D1-6(25.8 g) as a yellow solid. ¹H NMR: (400 MHz, CDCl₃) δ 5.84-5.77 (m,1H), 5.05-4.96 (m, 2H), 4.09-4.03 (d, J=24 Hz, 1H), 2.86 (s, 4H),2.12-2.06 (m, 2H), 1.58-1.51 (m, 2H), 1.33-1.27 (m, 3H), 1.09 (m, 1H),0.68-0.62 (m, 1H).Step 6. Preparation of D1-7: To a solution of D1-6 (10 g, 0.0374 mol) inTHF (374 mL) was added L-tert-leucine methyl ester hydrochloride (10.2g, 0.056 mol) and TEA (11.3 g, 0.112 mol). The solution was stirredovernight at 40° C. The mixture was concentrated in vacuo. The residuewas diluted with EtOAc and washed with water and brine, dried overanhydrous sodium sulfate, filtered and concentrated in vacuo. Theresidue was purified by silica gel chromatography to afford D1-7 (10.2g) as a yellow oil. LCMS-ESI (m/z): [M+H]⁺ calcd for C₁₆H₂₈NO₄: 298.2.found: 298.0.Step 7. Preparation of Intermediate D1: A solution of D1-7 (20 g, 0.067mol) in 2:1 mixture of MeOH/H₂O (447 mL/223 mL) was treated withLiOH*H₂O (11.3 g, 0.269 mol) and then heated at 60° C. for 4 h. Thereaction mixture was cooled, concentrated to half volume and extractedwith MTBE. Then the aqueous solution was acidified with aqueous 1 N HCl(400 mL) and extracted with EtOAc (400 mL×3), the combined organiclayers were washed with brine, dried over Na₂SO₄, filtered andconcentrated to afford Intermediate D1 (18 g). ¹H NMR: (400 MHz, CDCl₃)δ 10.5-9.4 (br, 1H), 5.82-5.71 (m, 1H), 5.20-5.17 (m, 1H), 4.99-4.91 (m,2H), 4.19-4.16 (m, 1H), 3.86-3.68 (m, 1H), 2.09-2.03 (m, 2H), 1.53-1.32(m, 2H), 1.30-1.20 (m, 2H), 1.18-1.13 (m, 1H), 1.11-0.99 (s, 9H),0.80-0.75 (m, 1H), 0.49-0.47 (m, 1H).

Preparation of Intermediate D2.

Step 1. Preparation of Intermediate D2: To a suspension of D1-6 (600 mg,2.25 mmol) and (S)-2-amino-2-cyclopentylacetic acid hydrochloride salt(386 mg, 2.7 mmol, Betapharma Inc.) in THF (20 mL) were added distilledwater (6 mL) and triethylamine (0.94 mL, 6.74 mmol). The homogeneoussolution was allowed to stir for ˜18 h. The THF was evaporated and theaqueous residue was diluted with water (20 mL). The mixture was basifiedwith 1 N NaOH (pH>10) and then washed twice (20 mL) with ethyl acetate.The aqueous phase was then acidified with 1 N HCl (pH<2) and theresulting solution was extracted twice (20 mL) with ethyl acetate. Thecombined organic phase was dried over anhydrous MgSO₄ and concentratedto afford Intermediate D2 (500 mg) as a brown oil. This was used withoutpurification in a subsequent step. LCMS-ESI (m/z): [M+H]⁺ calcd forC₁₆H₂₆NO₄: 296.2. found: 296.3.

Preparation of Intermediate D3.

Step 1. Preparation of Intermediate D3: To a suspension of D1-6 (800 mg,3 mmol) and (S)-2-amino-2-cyclohexylacetic acid (519 mg, 3.3 mmol; AlfaAesar) in water (15 mL) was added K₃PO₄ (1.27 g, 6 mmol). Thehomogeneous solution was allowed to stir at rt for 5 h. To the reactionmixture was charged with water (15 mL) and EtOAc (15 mL). The organiclayer was separated, and the aqueous layer was extracted with EtOAc (10mL). Organic layers were combined, washed with 1 N HCl, H₂O and brine,and dried over Na₂SO₄. Concentration of the organic solution affordedIntermediate D3 (850 mg) as an oil that was used subsequently withoutfurther purification. LCMS-ESI (m/z): [M+H]⁺ calcd for C₁₇H₂₈NO₄: 310.4.found: 310.3.

Preparation of Intermediate D4.

Step 1. Preparation of D4-2: Bicyclic alcohol D4-1 (2.9 g, 29.5 mmol,prepared according to Section A, Intermediate 1 of U.S. Pat. No.8,178,491 B2 (hereinafter “US '491”), p 192.) was dissolved in DCM (60mL) and TEA (8.2 mL, 59 mmol) was added. The stirred solution was cooledto 0° C. and MsCl (3.4 mL, 44 mmol) was added. The reaction mixture wasallowed to warm to rt gradually. After 18 h, the reaction mixture waspoured into H₂O. The aqueous layer was extracted 2× with DCM then thecombined organics were dried over MgSO₄, filtered and concentrated underreduced pressure. The crude material was purified by silica gelchromatography (20% to 50% EtOAc/Hex) to afford D4-2 (3.73 g).Step 2. Preparation of D4-3: NaH (1.69 g, 42.3 mmol) was suspended in100 mL THF and the mixture was cooled to 0° C. Diethyl malonate (6.4 mL,47 mmol) was added dropwise over 4 min and the stirred mixture waswarmed to rt. After another hour, mesylate D4-2 (3.73 g, 21.2 mmol) in20 mL THF was added and the reaction mixture was heated to reflux for 15h. After this period, the reaction mixture was cooled to rt and pouredinto saturated aqueous NaHCO₃. The aqueous layer was extracted 2× withEtOAc. Then, the organics were dried over MgSO₄, filtered andconcentrated under reduced pressure. The crude material was purified bysilica gel chromatography (0% to 15% EtOAc/Hex) to afford D4-3 (4.64 g).Step 3. Preparation of D4-4: Malonate D4-3 (4.64 g, 19.3 mmol) wasdissolved in 20 mL DMSO then NaCl (1.24 g, 21.2 mmol) and water (0.694mL, 38.6 mmol) were added. The stirred mixture was heated to 170° C. for48 h then cooled to rt and diluted with Et₂O. The organic solution waswashed with H₂O twice, then brine, dried over MgSO₄, filtered andconcentrated under reduced pressure. The crude material was purified bysilica gel chromatography (5% to 15% EtOAc/Hex) to afford D4-4 (2.83 g).Steps 4 and 5. Preparation of D4-5: A solution of ethyl ester D4-4 (2.83g, 16.8 mmol) and LiOH (1 M in H₂O, 34 mL, 34 mmol) in EtOH (68 mL) wasstirred at rt o/n then concentrated under reduced pressure to removeEtOH. The remaining material was diluted with H₂O and washed twice withDCM. The aqueous phase was acidified to pH 1-2 with 10% HCl and thenextracted three times with DCM. This DCM solution was dried over MgSO₄,filtered and concentrated under reduced pressure. The resulting crudecarboxylic acid was dissolved in DCM (100 mL) and treated with DMF (5drops). Oxalyl chloride (2.2 mL, 25 mmol) was added carefully. Afterstirring o/n, the reaction mixture was concentrated under reducedpressure to afford D4-5, which was carried on without furtherpurification.Step 6. Preparation of D4-6: (S)-4-Benzyl-2-oxazolidinone (3.57 g, 20.2mmol) was dissolved in THF (80 mL) and cooled to −78° C. n-BuLi (1.6 Min hexane, 12.6 mL, 20.2 mmol) was added dropwise over 7 min and thereaction mixture was allowed to stir at −78° C. for 30 min. Thissolution, containing the lithiated oxazolidinone was then added bycannula to a −78° C. solution of acid chloride D4-5 (16.8 mmol) in THF(80 mL) over 6 min. After stirring at −78° C. for an additional 30 min,the reaction mixture was quenched by addition of 1 M aqueous NaHSO₄. Theaqueous phase was extracted with EtOAc and the organic layer was driedover MgSO₄, filtered and concentrated under reduced pressure. The crudematerial was purified by silica gel chromatography (10% to 40%EtOAc/Hex) to afford D4-6 (4.32 g). LCMS-ESI (m/z): [M+H]⁺ calcd forC₁₈H₂₂NO₃: 300.16. found: 300.14.Step 7. Preparation of D4-7: A solution of KHMDS (0.5 M in PhMe, 3.4 mL,1.7 mmol) in THF (5 mL) was cooled to −78° C. and a separate −78° C.solution of oxazolidinone D4-6 (465 mg, 1.55 mmol) in THF (5 mL) wasadded dropwise by cannula. After 30 min, a −78° C. solution of trisylazide (576 mg, 1.86 mmol) in THF (5 mL) was added by cannula. Three minlater, the reaction was quenched by addition of AcOH (0.41 mL, 7.13mmol) and the reaction mixture was heated to 30° C. for 2 h. Aftercooling, the mixture was poured into brine. The aqueous layer wasextracted three times with DCM. The combined organics were dried overMgSO₄, filtered and concentrated under reduced pressure. The crudematerial was purified by silica gel chromatography (4% to 25% EtOAc/Hex)to afford azide D4-7 (367 mg). LCMS-ESI (m/z): [M+H]⁺ calcd forC₁₈H₂₁N₄O₃: 341.16. found: 341.10.Step 8. Preparation of D4-8: Azide D4-7 (367 mg, 1.08 mmol) anddi-tert-butyl dicarbonate (471 mg, 2.16 mmol) were dissolved in EtOAc(20 mL). 10% Pd/C (197 mg) was added and the atmosphere replaced withH₂. The suspension was stirred under 1 atm H₂ for 20 h, then filteredover Celite and concentrated under reduced pressure. The crude residuewas purified by silica gel chromatography (15% to 30% EtOAc/Hex) toafford D4-8 (376 mg). LCMS-ESI (m/z): [M-(t-Bu)+H]⁺ calcd forC₁₉H₂₃N₂O₅: 359.16. found: 359.43.

Steps 9 and 10. Preparation of D4-9: Carbamate D4-8 (376 mg, 0.907 mmol)was dissolved in THF (9 mL) and cooled to 0° C. H₂O₂(30% in H₂O, 0.463mL, 4.54 mmol) and LiOH (1M in H₂O, 2.7 mL, 2.7 mmol) were added. Thereaction was allowed to stir at 0° C. for another 2 h and was thenconcentrated under reduced pressure. The resulting concentrate waspoured into H₂O and the aqueous solution was washed twice with Et₂O,then acidified to pH 1-2 and extracted three times with DCM. Thecombined extracts were dried over MgSO₄, filtered and concentrated underreduced pressure. The resulting crude residue was dissolved in DCM (8mL) and MeOH (1 mL) and treated with trimethylsilyldiazomethane (2 M inhexane, 0.9 mL, 1.8 mmol). After stirring for 40 min at rt, the reactionwas quenched by addition of 10% AcOH/MeOH and concentrated under reducedpressure. The residue was purified by silica gel chromatography (4% to25% EtOAc/Hex) to afford D4-9 (167 mg). ¹H NMR (400 MHz, CDCl₃) δ 4.98(d, J=7.8 Hz, 1H), 4.22 (t, J=7.0 Hz, 1H), 3.70 (s, 3H), 1.89 (m, 1H),1.77-1.46 (m, 4H), 1.42 (s, 9H), 1.22 (m, 2H), 0.28 (dd, J=7.2 Hz, 13.3Hz, 1H), 0.13 (d, J=3.7 Hz, 1H).

Step 11. Preparation of D4-10: Carbamate D4-9 (223 mg, 0.828 mmol) wasdissolved in DCM (4 mL) and treated with HCl (4.0 M in dioxane, 1 mL,4.0 mmol). After stirring at rt for 17 h, the reaction mixture wasconcentrated under reduced pressure to afford amine hydrochloride saltD4-10, which was carried on without purification. LCMS-ESI (m/z): [M+H]⁺calcd for C₉H₁₆NO₂: 170.12. found: 170.04.Steps 12 and 13. Preparation of Intermediate D4: Amine hydrochloridesalt D4-10 (0.828 mmol, theoretical) in H₂O (1.4 mL) was treated with afreshly prepared solution of D1-6 (1.35 mmol) in DMF (1.4 mL). K₃PO₄(703 mg, 3.31 mmol) was added and the reaction mixture was stirred for 2h at rt. After dilution with EtOAc, the organic layer was washed with10% aqueous HCl and brine, then dried over MgSO₄, filtered andconcentrated under reduced pressure. The residue was purified by silicagel chromatography (0% to 25% EtOAc/Hex) to afford the expectedcarbamate (239 mg). LCMS-ESI (m/z): [M+H]⁺ calcd for C₁₈H₂₈NO₄: 322.20.found: 323.00. This material (239 mg, 0.744 mmol) was dissolved in MeOHand treated with LiOH (1.0 M in H₂O, 5.0 mL, 5.0 mmol). After stirringat rt for 1 h, the MeOH was removed under reduced pressure. The aqueoussolution was acidified to pH 1-2 with 10% aqueous HCl and was extractedthree times with DCM. The combined organics were dried over MgSO₄,filtered and concentrated under reduced pressure to afford IntermediateD4 (229 mg). LCMS-ESI⁺ (m/z): [M+H]⁺ calcd for C₁₇H₂₆NO₄: 308.2. found:307.9.

Preparation of Intermediate D5.

Intermediate D5 was prepared according to the procedure detailed in Li,H., et al. Synlett 2011, 10, 1454.Preparation of Intermediate mixture D6.

Step 1. Preparation of diastereomeric carbamate mixture D6-1:Intermediate C2 (1.34 g, 6.31 mmol),(±)-trans-1-methyl-2-(pent-4-enyl)cyclopropanol (590 mg, 4.208 mmol;prepared according to procedure for Intermediate C3, WO2011014487, p.36), DMAP (514 mg, 4.21 mmol), and DIPEA (2.93 mL, 16.83 mmol) werecombined in toluene (14 mL). The reaction was heated at 90° C. for 18 h.The reaction was diluted with Et₂O (25 mL) and 1 N aqueous HCl (75 mL),stirred well, and organics were removed. The aqueous layer was extractedthree times with ether (50 mL), the organics were combined, washed withbrine, dried over MgSO₄, filtered, and concentrated to give a crude oil,which was purified via silica gel chromatography to give 1:1diastereomeric mixture D6-1 as a clear oil (820 mg). LCMS-ESI⁺ (m/z):[M+Na]⁺ calcd for C₂₀H₃₅NNaO₄: 376.3. found: 376.2.Step 2: Preparation of diastereomeric Intermediate mixture D6. Thediastereomeric mixture D6-1 was taken up in DCM (2 mL) and treated withTFA (2 mL) at room temperature. After 1.5 h, the reaction wasconcentrated in vacuo and co-evaporated with chloroform repeatedly toremove residual TFA and purified via silica gel chromatography to give1:1 diastereomeric mixture of Intermediate D6 as a brown oil, (536 mg).LCMS-ESI⁺ (m/z): [M+Na]⁺ calcd for C₁₆H₂₇NNaO₄: 320.2. found: 320.1.

Preparation of Intermediate D7.

Step 1. Preparation of D7-1:(1R,2R)-1-methyl-2-(pent-4-enyl)cyclopentanol (220.9 mg, 1.313 mmol;prepared according to procedure for Intermediate B26, InternationalPatent Publication No. WO 2008/057209 (hereinafter “WO '209”), p. 45)and Intermediate C1 (337.1 mg, 1.969 mmol) were treated with DIPEA (0.91mL, 5.252 mmol) and DMAP (160.4 mg, 1.313 mmol) in toluene (4.4 mL). Themixture was heated at 85° C. for 21 h. The solution was diluted withether (80 mL). The solution was washed with 1 N aqueous HCl (30 mL) andbrine (30 mL) successively. Obtained organic layer was dried overNa₂SO₄. After removal of drying agent by a filtration, the solvent wasremoved under reduced pressure. The residue was purified by silica gelchromatography (13% ethyl acetate in hexanes) to give D7-1 (249.5 mg,0.735 mmol) as colorless oil. ¹H NMR (300 MHz, CDCl₃, rotamers expressedas total H value×fraction present) δ 5.76-5.92 (m, 1H), 5.12 (d, J=9.6Hz, 1H), 5.02 (d, J=16.8 Hz, 1H), 4.96 (d, J=9.6 Hz, 1H), 4.13 (d, J=9.6Hz, 1H), 3.81 (s, 3×4/10H), 3.73 (s, 3×6/10H), 1.80-2.15 (m, 7H),1.04-1.74 (m, 6H), 1.36 (s, 3H), 1.04 (s, 9×4/10H), 0.97 (s, 9×6/10H).Step 2. Preparation of Intermediate D7: Ester D7-1 (249.5 mg, 0.735mmol) was treated with 2 M aqueous LiOH aqueous solution (2 mL, 4.0mmol) in MeOH/THF (4 mL/4 mL) at rt for 25 h. The reaction mixture wasthen treated with 1 N aqueous HCl (5 mL) and aqueous brine (25 mL) toslightly acidify. The mixture was extracted three times with CH₂Cl₂ (30mL). The organic layer was washed with aqueous brine (30 mL). Obtainedorganic layer was dried over Na₂SO₄. After removal of drying agent byfiltration, the solvent was removed under a reduced pressure to giveIntermediate D7 (191.2 mg, 0.587 mmol) as a colorless oil which was usedsubsequently without further purification. ¹H NMR (300 MHz, CDCl₃) b9.00 (br s, 1H), 5.72-5.90 (m, 1H), 5.12 (d, J=9.6 Hz, 1H), 5.00 (d,J=16.8 Hz, 1H), 4.94 (d, J=9.6 Hz, 1H), 4.13 (d, J=9.6 Hz, 1H),1.80-2.16 (m, 7H), 1.04-1.74 (m, 6H), 1.35 (s, 3H), 1.02 (s, 9H).Preparation of Intermediate mixture D8.

Step 1. Preparation of D8-2: To a solution of intermediate D8-1 (500 mg,3.24 mmol, prepared according to WO '209, p. 36) in DCM (6.65 mL) wasadded Dess-Martin periodinane (1.37 g, 3.24 mmol) at rt under an argonatmosphere. After 6 h, the reaction mixture was filtered through a padof Celite and was directly purified by silica gel chromatography (0-100%ethyl acetate/hexanes gradient) to afford ketone D8-2 (252 mg) as acolorless oil. ¹H NMR (400 MHz, CDCl₃) δ 5.81 (ddt, J=16.9, 10.2, 6.6Hz, 1H), 5.05-4.92 (m, 2H), 2.38-1.93 (m, 7H), 1.87-1.68 (m, 2H),1.60-1.37 (m, 3H), 1.35-1.20 (m, 1H).Step 2. Preparation of diastereomeric mixture D8-3: To a solution ofketone D8-2 (385 mg, 2.53 mmol) and TMSCF₃ (749 μL, 5.07 mmol) in THF(2.3 mL) was added CsF (7.0 mg, 46 μmol) at rt under an argonatmosphere. After 2.5 h, the reaction mixture was diluted with water (10mL) and the resulting mixture was extracted twice with DCM (10 mL). Thecombined organic layers were dried over anhydrous sodium sulfate, andwere concentrated in vacuo. The crude residue was purified by silica gelchromatography (0-100% ethyl acetate/hexanes gradient) to afford silylether D8-3 (714 mg, 1:1 diastereomeric mixture) as a colorless oil. ¹HNMR (400 MHz, CDCl₃) δ 5.67 (ddt, J=13.3, 10.1, 6.7 Hz, 1H), 4.91-4.76(m, 2H), 2.02-1.00 (m, 13H), 0.00 (s, 9H).Step 3. Preparation of diastereomeric mixture D8-4: To a solution ofD8-3 (700 mg, 2.38 mmol) in THF (11.9 mL) was added TBAF (1M in THF,2.38 mL, 2.38 mmol) at rt under an argon atmosphere. After 30 min, thereaction mixture was diluted with dichloromethane (100 mL). Theresulting mixture was washed with saturated aqueous sodium bicarbonatesolution (75 mL), was dried over anhydrous sodium sulfate, and wasconcentrated in vacuo. The crude residue was purified by silica gelchromatography (0-100% ethyl acetate/hexanes gradient) to afford alcoholD8-4 (418 mg, 1:1 diastereomeric mixture) as a colorless oil. ¹H NMR(400 MHz, CDCl₃) δ 5.81 (dt, J=16.8, 6.6 Hz, 1H), 5.09-4.88 (m, 2H),2.20-1.91 (m, 4H), 1.86-1.08 (m, 10H).Step 4. Preparation of diastereomeric mixture D8-5: A solution of D8-4(380 mg, 1.72 mmol), Intermediate C1 (295.7 mg, 1.72 mmol), DIPEA (1.20mL, 6.88 mmol), and DMAP (210 mg, 1.72 mmol) in toluene (8.6 mL) washeated to 85° C. under an argon atmosphere. After 20 h, the reactionmixture was allowed to cool to rt and was diluted with ethyl acetate(100 mL). The resulting mixture was washed with 1 N HCl solution (50mL), saturated aqueous sodium bicarbonate solution (50 mL), and brine(50 mL). The organic layer was dried over anhydrous sodium sulfate, andwas concentrated in vacuo. The crude residue was purified by silica gelchromatography (0-100% ethyl acetate/hexanes gradient) to affordcarbamate D8-5 (550 mg, 1:1 diastereomeric mixture) as a colorless oil.¹H NMR (400 MHz, CDCl₃) δ 5.81 (ddt, J=16.7, 9.8, 6.6 Hz, 1H), 5.37 (d,J=9.4 Hz, 1H), 5.06-4.89 (m, 2H), 4.16-4.07 (m, 1H), 3.75 (s, 3H),2.84-2.29 (m, 2H), 2.27-1.89 (m, 3H), 1.85-1.12 (m, 8H), 0.98 (s, 9H).Step 5. Preparation of diastereomeric Intermediate mixture D8: To asolution of carbamate D8-5 (500 mg, 1.27 mmol) in DCE (6.4 mL) was addedtrimethyltin hydroxide (2.30 g, 12.7 mmol) at rt under an argonatmosphere, and the resulting mixture was heated to 65° C. After 21 h,the reaction mixture allowed to cool to rt and was diluted with 1 N HClsolution (50 mL). The resulting mixture was extracted with ethyl acetate(2×50 mL). The combined organic extracts were dried over anhydroussodium sulfate and were concentrated in vacuo to afford Intermediate D8(575 mg, 1:1 diastereomeric mixture) as a colorless oil, which was usedsubsequently without further purification. ¹H NMR (400 MHz, CDCl₃) b5.90-5.71 (m, 1H), 5.32 (d, J=9.3 Hz, 1H), 5.07-4.89 (m, 2H), 4.16 (d,J=9.8 Hz, 1H), 2.83-2.30 (m, 2H), 2.27-1.87 (m, 3H), 1.83-1.12 (m, 8H),1.04 (s, 9H).Preparation of Intermediate mixture D9 and D10.

Steps 1 and 2: Preparation of racemate D9-1: Magnesium metal (1.32 g,54.3 mmol) was added to a 2-neck flask fitted with a reflux condenserand the vessel was flushed with Ar. THF (42 mL) was added followed byiodine (ca. 5 mg). The stirred suspension was heated to 45° C. and5-bromopent-1-ene was added (1.2 g, 8.1 mmol) in one portion. Afterstirring several minutes, additional 5-bromopent-1-ene (5.5 g, 37 mmol)was added at a rate sufficient to maintain gentle reflux. The resultingmixture was stirred at 50° C. for 15 min and was then cooled to ambienttemperature and used immediately in the following step. A suspension ofCuI (630 mg, 3.3 mmol) in THF (24 mL) under Ar was cooled to −5 OC. Analiquot of pent-4-enylmagnesium bromide (ca. 0.95 M, 20 mL, 19 mmol)prepared in step 1 was added over 5 min, and the resulting mixture wasstirred for an additional 15 min. The reaction mixture was then cooledto −20° C., and (±)-exo-2,3-epoxynorbornane (1.5 g, 14 mmol) was addedas a solution in THF (5 mL) over 1 min. Two additional portions of THF(2.5 mL each) were used to ensure complete transfer, and the resultingmixture was stirred for 20 min. The reaction was then removed from thecold bath and warmed to rt. After stirring an additional 1.75 h, thereaction was quenched with saturated aqueous NH₄Cl (5 mL) and wasfiltered with EtOAc (100 mL) and H₂O (100 mL) through Celite. The phaseswere separated, and the organic phase was dried over Na₂SO₄, filtered,and concentrated to afford (±)-D9-1 as a colorless residue (813 mg). ¹HNMR (300 MHz, CDCl₃) δ 5.90-5.67 (m, 1H), 5.04-4.86 (m, 2H), 3.12 (s,1H), 2.20-1.92 (m, 5H), 1.69-1.57 (m, 1H), 1.55-1.12 (m, 9H), 1.03-0.84(m, 1H).Step 3. Preparation of diastereomeric Intermediate mixture D9 and D10:Alcohol mixture (±)-D9-1 (813 mg, 4.51 mmol) was dissolved in DMF (4.5mL). Pyridine (370 μL, 4.5 mmol) was added followed by DSC (1.5 g, 5.8mmol). The reaction mixture was heated to 45° C. and was stirred for 4h. The reaction mixture was then cooled to 0° C. and water (4.5 mL) wasadded dropwise over 2 min. The reaction mixture was stirred for 5 minand was removed from the cold bath. After an additional 5 min, thereaction mixture was cooled to 0° C. and L-tert-leucine (835 mg, 6.37mmol) and K₃PO₄ (2.70 g, 12.7 mmol) were added. The mixture was stirredfor 10 min and was removed from the cold bath. After stirring anadditional 24 h, the mixture was diluted with EtOAc (30 mL), acidifiedwith 1 M aqueous HCl (15 mL), and diluted with 0.2 M aqueous HCl (15mL). The phases were separated, and the organic phase was washed with0.2 M aqueous HCl (2×20 mL), dried over Na₂SO₄, filtered, andconcentrated to afford diastereomeric Intermediate mixture D9 and D10(1.64 g). LCMS-ESI⁻ (m/z): [M−H]⁻ calcd for C₁₉H₃₀NO₄: 336.2. found:336.0.

Preparation of Intermediate D11.

Step 1. Preparation of 011-1: To a mixture of 01 (1.0 g, 3.53 mmol),sodium periodate (2.26 g, 10.59 mmol) in 24 mL THF and 12 mL water wasadded Os EnCat™ 40 (0.25 mmol/g loading, 282 mg, 0.071 mmol,Sigma-Aldrich). The mixture was stirred for 3 days. Water (50 mL) wasadded and the mixture was filtered. The filter cake was washed withwater (total volume 400 mL) and ethyl acetate (total volume 600 mL). Thefiltrate layers were separated. The organic phase was dried over sodiumsulfate, filtered and concentrated to give 011-1 (1.56 g) which was usedwithout further purification. LCMS-ESI⁺ (m/z): [M+H]⁺ calcd forC₁₄H₂₄NO₅: 286.2 found: 286.1.Step 2. Preparation of D11-2: To a solution of 011-1 (3.05 g, 10.7 mmol)in MeOH (50 mL) at 0° C. was added sodium borohydride in portions (809mg, 21.4 mmol). The reaction mixture was stirred at rt for 6 h. Themixture was diluted with 50 mL ethyl acetate and 50 mL brine and thelayers were separated. The organic phase was extracted with two 25 mLportions of ethyl acetate. The combined organic phase was dried oversodium sulfate, filtered and concentrated. The crude product mixture waspurified by silica gel chromatography (EtOAc in hexanes: 10% to 100%) togive 011-2 (380 mg). LCMS-ESI⁺ (m/z): [M+H]⁺ calcd for C₁₄H₂₆NO₅: 288.2.found: 288.1.Step 3. Preparation of Intermediate D11: To a solution of D11-2 (283 mg,0.98 mmol) in THF (2.8 mL) at 0° C. was added1-nitro-2-selenocyanatobenzene (336 mg, 1.47 mmol) and tributylphosphine(363 μL, 1.47 mmol). The cooling bath was removed and the mixture wasstirred for 25 minutes at rt. The reaction was again cooled to 0° C. andwas treated with 30% hydrogen peroxide solution (0.665 mL, 5.85 mmol)and stirred for 1 h at rt and then heated at 60° C. for 1 h. Thereaction was diluted with EtOAc and the desired product was extractedinto aqueous sodium bicarbonate. The bicarbonate extract was acidifiedwith 2 N HCl and extracted with ethyl acetate. The organic phase wasdried over sodium sulfate and concentrated to give Intermediate D11 (136mg). LCMS-ESI (m/z): [M+H]⁺ calcd for C₁₄H₂₄NO₄: 270.2. found: 270.1.Preparation of Intermediate mixture D12 and D13.

Step 1: Preparation of D12-1: To a solution of K₂Cr₂O₇(121 g, 0.41 mol)in H₂O (1.5 L) was added dropwise H₂SO₄ (143 g, 1.46 mol) at rt and themixture was stirred for 1 h. The mixture was then cooled to 0° C. andD4-1 (80 g, 0.814 mol; prepared according to Section A, Intermediate 1of US '491, p 192.) in MTBE (1.5 L) was added dropwise. The reactionmixture was stirred at rt for 2 h. The aqueous phase was extracted withMTBE (3×500 mL), dried over MgSO₄, filtered, and concentrated in vacuo.The crude product was purified by distillation (20 mmHg, bp: 60-62° C.)to provide D12-1 as a pale yellow liquid (60 g). ¹H NMR (400 MHz, CDCl₃)δ 2.57-2.63 (m, 2H), 2.14-2.19 (d, J=20 Hz, 2H), 1.52-1.57 (m, 2H),0.89-0.94 (m, 1H), −0.05-−0.02 (m, 1H).Step 2: Preparation of (±)-D12-2: Under Ar, a mixture of THF (4.4 mL)and HMPA (1.8 mL) was cooled to −78° C. A 1 M solution of LiHMDS in THF(2.2 mL, 2.2 mmol) was added. Ketone D12-1 (202 mg, 2.10 mmol) was addedas a solution in THF (2 mL) over 1 min, washing with additional THF (2×1mL) to ensure complete transfer. After 25 min, 5-iodopent-1-ene(prepared according to Jin, J. et. al. J. Org. Chem. 2007, 72,5098-5103) (880 mg, 4.5 mmol) was added over 30 s by syringe. After 10min, the reaction was placed in a cold bath at −45° C. and was warmed to−30° C. over 1.5 h. The reaction was quenched with saturated aqueousNH₄Cl (15 mL) and was diluted with EtOAc (30 mL) and H₂O (15 mL). Thephases were separated, and the aqueous phase was extracted with EtOAc(30 mL). The combined organics were dried over Na₂SO₄, filtered, andconcentrated to afford a crude residue that was purified by silica gelchromatography (0% to 15% EtOAc in hexanes) to provide (+/−)-D12-2 acolorless oil (162 mg). ¹H NMR (400 MHz, CDCl₃) 5.82-5.67 (m, 1H),5.03-4.87 (m, 2H), 2.61-2.51 (m, 1H), 2.11 (d, J=19.1 Hz, 1H), 2.08-1.99(m, 3H), 1.61-1.40 (m, 5H), 1.36-1.28 (m, 1H), 0.92-0.81 (m, 1H),−0.03-−0.11 (m, 1H).Step 3: Preparation of (±)-D12-3 and (±)-D12-4: A solution of (±)-D12-2(142 mg, 0.865 mmol) in THF (4 mL) was cooled to −78° C. A 1 M THFsolution of LiBHEt₃ (1.3 mL, 1.3 mmol) was added dropwise over 30 s. Thereaction was stirred 15 min and was removed from the cold bath. Afterwarming to rt (15 min), the reaction was quenched with saturated aqueousNH₄Cl (1 mL). The resulting mixture was diluted with Et₂O (20 mL) andH₂O (20 mL). The phases were separated, and the aqueous phase wasextracted with Et₂O (20 mL). The combined organics were dried overMgSO₄, filtered, and concentrated to a crude residue. Purification bysilica gel chromatography (0% to 10% EtOAc in hexanes) provided 133 mgof a mixture of diastereomers (±)-D12-3 and (±)-D12-4. The combinedmaterial from two experiments (253 mg) was further purified by silicagel chromatography (0% to 15% EtOAc in hexanes) to provide (±)-D12-3(150 mg) and (±)-D12-4 (58 mg) as colorless oils. ¹H NMR for (±)-D12-3(300 MHz, CDCl₃) δ 5.91-5.69 (m, 1H), 5.07-4.88 (m, 2H), 3.97 (d, J=6.7Hz, 1H), 2.19-1.99 (m, 3H), 1.84-1.73 (m, 1H), 1.62 (d, J=14.1 Hz, 1H),1.54-1.40 (m, 2H), 1.32-1.17 (m, 3H), 1.16-1.06 (m, 1H), 0.60-0.43 (m,2H). ¹H NMR for (±)-D12-4 (300 MHz, CDCl₃) δ 5.95-5.73 (m, 1H),5.09-4.88 (m, 2H), 4.05-3.86 (m, 1H), 2.17-1.84 (m, 4H), 1.72-1.34 (m,5H), 1.28-1.08 (m, 3H), 0.49-0.36 (m, 1H), 0.21-0.11 (m, 1H).Step 4: Preparation of diastereomeric Intermediate mixture D12 and D13:A mixture of (±)-D12-3 (150 mg, 0.90 mmol) was dissolved in DMF (1.0mL). Pyridine (75 μL, 0.92 mmol) and DSC (302 mg, 1.18 mmol) were added,and the reaction was stirred at 45° C. for 21.5 h. The reaction was thenplaced in an ice water bath and H₂O (1.0 mL) was added dropwise viasyringe over 1 min. The mixture was removed from the cold bath andallowed to stir 5 min. The mixture was re-cooled in an ice water bathand L-tert-leucine (154 mg, 1.17 mmol) was added followed by K₃PO₄ (502mg, 2.36 mmol). The reaction mixture was removed from the cold bath andallowed to stir at rt for 24 h. The mixture was then diluted with EtOAc(40 mL) and 1 M aqueous HCl (20 mL). The phases were separated, and theaqueous phase was extracted with EtOAc (30 mL). The combined organicphase was washed with 0.2 M aqueous HCl (2×20 mL), dried over MgSO₄,filtered, and concentrated to afford diastereomeric Intermediate mixtureD12 and D13 (300 mg) as a colorless oil. LCMS-ESI⁻ (m/z): [M−H]⁻ calcdfor C₁₈H₂₈NO₄: 322.2. found: 322.0).

Preparation of Intermediate D12.

Step 1: Preparation of D12-5: To a solution of(1S,4R)-cis-4-acetoxy-2-cyclopent-1-ol (Aldrich, 10 g, 70.4 mmol),triethylamine (48.8 mL, 350 mmol), and DMAP (4.29 g, 35.2 mmol) indichloromethane (352 mL) was added pivaloyl chloride (10.8 mL, 87.75mmol) dropwise via syringe at 0° C. under an argon atmosphere. After 2h, the reaction mixture was diluted with saturated aqueous sodiumbicarbonate solution (500 mL), and extracted with dichloromethane (2×500mL). The combined organic extracts were dried over anhydrous sodiumsulfate and were concentrated in vacuo to afford D12-5 (15.0 g) as acolorless oil. ¹H NMR (300 MHz, CDCl₃) δ 6.08 (br s, 2H), 5.54 (td,J=8.0, 4.1 Hz, 2H), 2.88 (dt, J=14.9, 7.5 Hz, 1H), 2.07 (s, 3H), 1.69(dt, J=14.7, 4.1 Hz, 1H), 1.20 (s, 9H).Step 2: Preparation of D12-6: To a solution of D12-5 (15.0 g, 70.4 mmol)in methanol (352 mL) was added potassium carbonate (9.73 g, 70.4 mmol)at rt under an argon atmosphere. After 5 h, the reaction mixture wasfiltered and was concentrated in vacuo. The residue was dissolved intoethyl acetate (500 mL) and the resulting mixture was washed with water(500 mL) and brine (500 mL), dried over anhydrous sodium sulfate, andconcentrated in vacuo. The crude residue was purified by silica gelchromatography (0-100% ethyl acetate/hexanes) to afford D12-6 (12.0 g)as a colorless oil. ¹H NMR (300 MHz, CDCl₃) δ 6.11 (br d, J=5.5 Hz, 1H),5.97 (br d, J=5.6 Hz, 1H), 5.48 (br s, 1H), 4.73 (br s, 1H), 2.82 (dt,J=14.6, 7.3 Hz, 1H), 1.67 (s, 1H), 1.61 (dt, J=14.5, 4.0 Hz, 1H), 1.20(s, J=3.8 Hz, 9H).Step 3: Preparation of D12-7: To a solution of copper(I) cyanide (5.10g, 57.0 mmol) in diethyl ether (95 mL) was added pent-4-enylmagnesiumbromide (Novel Chemical Solutions, 0.5 M in THF, 114 mL, 57.0 mmol)dropwise via cannula over a 30 min period at 0° C. under an argonatmosphere. After 10 min, a solution of D12-6 (3.50 g, 19.0 mmol) indiethyl ether (10 mL) was added slowly via cannula. The reaction mixturewas then allowed to slowly warm to rt. After 16 h, the resulting mixturewas quenched with saturated aqueous ammonium chloride solution (400 mL)and the resulting mixture was extracted into ethyl acetate (2×400 mL).The combined organic phases were washed with brine (400 mL), dried overanhydrous sodium sulfate, and concentrated in vacuo. The crude residuewas purified by silica gel chromatography (0-100% ethyl acetate/hexanes)to afford D12-7 (2.4 g) as a colorless oil. ¹H NMR (400 MHz, CDCl₃) δ5.80 (ddt, J=16.9, 10.2, 6.7 Hz, 1H), 5.69 (dd, J=5.8, 1.7 Hz, 1H), 5.65(d, J=7.2 Hz, 1H), 5.00 (dd, J=17.1, 1.3 Hz, 1H), 4.94 (d, J=10.2 Hz,1H), 4.12-4.05 (m, 1H), 2.69 (ddd, J=17.2, 6.4, 1.5 Hz, 1H), 2.54-2.45(m, 1H), 2.24 (d, J=17.2 Hz, 1H), 1.69 (br s, 1H), 1.52-1.19 (m, 6H).Step 4: Preparation of (1S,2R,3R,5S)-D12-3: To a solution of D12-7 (20mg, 0.13 mmol), and diethyl zinc (1 M in hexanes, 132 μL, 0.132 mmol) indiethyl ether (0.66 mL) was added diiodomethane (21 μL, 0.26 mmol) at rtunder an argon atmosphere. After 2 h, the reaction mixture was quenchedwith 1 N aqueous HCl solution (0.66 mL). After 5 min, the resultingyellow mixture was diluted with saturated aqueous sodium bicarbonatesolution (5 mL) and the resulting mixture was extracted withdichloromethane (3×5 mL). The combined organic extracts were dried overanhydrous sodium sulfate solution, and were concentrated in vacuo. Thecrude residue was purified by silica gel chromatography (0-100% ethylacetate/hexanes) to afford (1S,2R,3R,5S)-D12-3 (10 mg) as a colorlessoil. ¹H NMR (400 MHz, CDCl₃) δ 5.83 (ddt, J=16.9, 10.2, 6.7 Hz, 1H),5.02 (d, J=17.2 Hz, 1H), 4.96 (d, J=11.3 Hz, 1H), 4.00 (d, J=6.7 Hz,1H), 2.19-2.02 (m, 3H), 1.82 (t, J=7.2 Hz, 1H), 1.64 (d, J=14.2 Hz, 1H),1.55-1.42 (m, 2H), 1.38-1.20 (m, 4H), 1.19-1.08 (m, 1H), 0.62-0.47 (m,2H).Step 5: Preparation of Intermediate D12: Alcohol (1S,2R,3R,5S)-D12-3(0.450 g, 2.7 mmol) was taken up in DMF (2.7 mL) and treatedsubsequently with DSC (0.92 g, 3.52 mmol) and pyridine (0.22 mL, 2.8mmol). The reaction was then heated to 50° C. o/n. The reaction was thencooled to 0° C. and water (5.5 mL) was added dropwise over 1 min. Theresulting opaque suspension was stirred at rt for 10 min beforerecooling to 0° C. The reaction was then treated subsequently withL-tert-leucine (0.462 g, 3.5 mmol) and K₃PO₄ (1.5 g, 7.0 mmol) andallowed to warm to rt overnight with vigorous stirring. The resultingopaque suspension was diluted with EtOAc and 1 M aqueous HCl. AdditionalHCl (12 M) was added dropwise to adjust the pH 3. The aqueous layer wasextracted with EtOAc and the combined organics were washed with brineand dried over anhydrous MgSO₄. Following concentration in vacuo,Intermediate D12 was obtained (1.72 g) as a viscous, colorless oil thatis contaminated with small amounts of DMF and EtOAc. The material wasused in subsequent reactions without further purification. LCMS-ESI(m/z): [M+H]⁺ calcd for C₁₈H₃₀NO₄: 324.2. found 324.7.

Preparation of Intermediate D14.

Step 1. Preparation of Intermediate D14. Carbonate D1-6 (862 mg, 3.23mmol) was treated with (S)-2-amino-2-(1-methylcyclopentyl)acetic acidhydrochloride (750 mg, 3.87 mmol; prepared according to Robl, J. A., etal. J. Med. Chem., 2004, 47, 2587), THF (28 mL), H₂O (8.4 mL) and TEA(1.4 mL, 9.7 mmol). The reaction mixture was stirred for 16 h and theTHF was removed in vacuo. The remaining material was diluted with H₂Oand the pH adjusted to ˜10-12 by addition of 10% aqueous NaOH. Theaqueous phase was washed twice with EtOAc and then acidified to pH 1-2with 10% aqueous HCl. The acidic solution was extracted 3× with EtOAc.The combined extractions were dried over anhydrous MgSO₄, filtered andconcentrated in vacuo. The initial EtOAc washings (of the basic aqueoussolution) were washed with 10% aqueous HCl, dried over MgSO₄, filteredand concentrated in vacuo. The combined concentrates were purified bysilica gel chromatography (50% to 100% EtOAc/Hex) to afford IntermediateD14 (980 mg). LCMS-ESI⁺ (m/z): [M+H]⁺ calcd for C₁₇H₂₈NO₄: 310.2. found310.0.Preparation of Intermediate mixture D15.

Step 1. Preparation of (±)-D15-1: To a solution of titanium(IV)isopropoxide (11.3 g, 40.0 mmol) in THF (160 mL) was added methylmagnesium bromide (3 M in Et₂O, 20 mL, 60.0 mmol) dropwise via syringeat rt under an argon atmosphere. After 10 min, the reaction mixture wascooled to 0° C. and a solution of methyl propionate (3.80 mL, 40.0 mmol)in THF (10 mL) was added slowly via syringe. After 5 min,hept-6-enylmagnesium bromide (Novel Chemical Solutions, 0.5 M in THF,160 mL, 80 mmol) was added dropwise via addition funnel over 1 h. After2.5 h, the reaction mixture was quenched with 10% aqueous sulfuric acid(100 mL) and the resulting mixture was extracted with diethyl ether(2×200 mL). The organic phase was dried over anhydrous sodium sulfateand was concentrated in vacuo. The crude residue was purified by silicagel chromatography (0-100% ethyl acetate/hexanes) to afford (±)-D15-1(3.03 g, 50%) as a colorless oil. ¹H NMR (300 MHz, CDCl₃) δ 5.77 (ddt,J=16.9, 10.2, 6.7 Hz, 1H), 5.03-4.86 (m, 2H), 2.04 (q, J=6.1 Hz, 2H),1.75-1.14 (m, 6H), 1.04 (t, J=7.4 Hz, 3H), 1.01-0.91 (m, 1H), 0.89-0.71(m, 2H), 0.02 (t, J=5.5 Hz, 1H).Step 2. Preparation of diastereomeric Intermediate mixture D15: Racemicalcohol mixture (±)-D15-1 (2.00 g, 13.0 mmol) was dissolved in DMF (13.0mL). Pyridine (1.05 mL, 13.0 mmol) was added followed by DSC (4.00 g,15.6 mmol). The reaction mixture was heated to 50° C. and was stirredfor 20 h. The reaction mixture was then cooled to rt and water (13 mL)was added dropwise over 2 min. L-tert-leucine (2.17 g, 13.0 mmol) andK₃PO₄ (8.28 g, 39.0 mmol) were then added and the reaction mixture waswarmed to 50° C. After 5 h, the reaction mixture was allowed to cool tort and was diluted with water (500 mL). The resulting mixture was washedwith dichloromethane (100 mL). The aqueous phase was then acidified topH 2 with 2 N aqueous HCl solution, and was extracted with DCM (2×400mL). The combined organic extracts were dried over anhydrous sodiumsulfate and were concentrated under reduced pressure to afforddiastereomeric Intermediate mixture D15 (4.5 g) as a pale orange oil,which was used subsequently without further purification.

Preparation of Intermediate D16:

Intermediate D16 was prepared in a similar fashion to the preparation ofIntermediate D12, substituting but-3-enylmagnesium bromide forpent-4-enylmagnesium bromide in Step 3. LCMS-ESI⁺ (m/z): [M+H]⁺ calcdfor C₁₇H₂₈NO₄: 310.2. found 310.8.

Preparation of Intermediate D17:

Step 1. Preparation of intermediate mixture D17.(±)-trans-1-methyl-2-(but-3-enyl)cyclopropanol (900 mg, 0.13 mmol),prepared according to procedure for Intermediate B2, InternationalPatent Publication No. WO 2012/40040 (hereinafter “WO '040”), p. 38, wasdissolved in DMF (6 mL). Pyridine (577 μL, 7.13 mmol) was added followedby DSC (2.37 g, 9.27 mmol). The reaction mixture was heated to 40° C.and was stirred for 18 h. The reaction mixture was then cooled to 0° C.and water (6 mL) was added dropwise over 5 min. The reaction mixture wasstirred for 5 min and was removed from the cold bath. After anadditional 5 min, the reaction mixture was cooled to 0° C. andL-tert-leucine (1.21 g, 9.27 mmol) and K₃PO₄ (4.69 g, 22.1 mmol) wereadded. The mixture was stirred for 10 min and was removed from the coldbath. After stirring an additional 6 h, the mixture was diluted withEtOAc (30 mL), acidified with 1 M aqueous HCl (25 mL), and diluted with0.2 M aqueous HCl (25 mL). The phases were separated, and the organicphase was washed with 0.2 M aqueous HCl (2×20 mL), dried over Na₂SO₄,filtered, and concentrated to afford diastereomeric carbamate mixtureD17 (2.10 g). LCMS-ESI⁺ (m/z): [M+Na]⁺ calcd for C₁₅H₂₅NNaO₄: 306.2.found: 306.1.

Preparation of Intermediate D18:

Step 1. Preparation of D18-1: (Prepared according to WO2011013141) To asolution of (S)-4-amino-2-hydroxybutanoic acid (15 g, 126 mmol) inmethanol (95 mL) was added concentrated sulfuric acid (8 mL), and thereaction was heated to reflux. After 18 h, the resulting mixture wasallowed to cool to room temperature and was concentrated in vacuo. Theresidue was slurried with ethyl acetate (95 mL) and D18-1 was collectedby vacuum filtration. ¹H NMR (400 MHz, CDCl₃) δ 5.69 (br s, 1H), 4.31(ddd, J=9.2, 8.1, 2.2 Hz, 1H), 3.49 (d, J=5.6 Hz, 1H), 3.41 (tt, J=9.2,1.7 Hz, 1H), 3.33 (td, J=9.4, 6.5 Hz, 1H), 2.81 (br s, 1H), 2.59-2.48(m, 1H), 2.09 (dq, J=12.9, 9.1 Hz, 1H).

Step 2. Preparation of D18-2: To a solution of D18-1 (4.5 g, 44 mmol),4-nitrobenzoic acid (8.19 g, 49 mmol), and triphenylphosphine (22.4 g,132 mmol) in tetrahydrofuran (220 mL) was added diisopropylazodicarboxylate (12.1 mL, 61.6 mmol) dropwise via syringe at 23° C.under an argon atmosphere. After 20 h, the resulting cloudy orangereaction mixture was concentrated in vacuo and methanol (200 mL)followed by potassium carbonate (15 g, 109 mmol) were added and thereaction was stirred at 23° C. After an additional 5 h, the resultingmixture was diluted with chloroform (200 mL) and was filtered. Thefiltrate was concentrated in vacuo and the crude residue was taken upinto water (150 mL) and 1N aqueous hydrochloric acid solution (50 mL).The aqueous layer was washed with ethyl acetate (3×200 mL) to removeorganic by-products, and was concentrated in vacuo to crude afford D18-2that was used directly in the next step. ¹H NMR (300 MHz, CD₃OD) δ 4.28(t, J=8.4 Hz, 1H), 3.43-3.20 (m, 1H), 2.56-2.39 (m, 1H), 1.96 (dq,J=12.7, 8.7 Hz, 1H).

Step 3. Preparation of D18-3: To a solution of crude D18-2 (5 g, 49.5mmol) and imidazole (3.4 g, 49.5 mmol) in DMF (247 mL) was added TBSCl(7.5 g, 49.5 mmol) at 0° C. under an argon atmosphere. The resultingmixture was allowed to warm to 23° C. After 7 h, additional imidazole (7g, 102 mmol) and TBSCl (16 g, 106 mmol) were added sequentially. Afteran additional 16 h, the resulting mixture was diluted with 1N aqueoushydrochloric acid solution (1 L) and was extracted with ethyl acetate (1L). The organic layer was split and was washed with brine (1 L), wasdried with anhydrous sodium sulfate, and was concentrate in vacuo. Thecrude residue was purified by silica gel chromatography (0-100% ethylacetate/hexanes gradient) to afford D18-3. ¹H NMR (300 MHz, CDCl₃) δ5.99 (s, 1H), 4.26 (t, J=7.7 Hz, 1H), 3.44-3.33 (m, 1H), 3.30-3.19 (m,1H), 2.45-2.29 (m, 1H), 2.11-1.95 (m, 1H), 0.91 (s, 9H), 0.02 (s, 3H),0.00 (s, 3H).

Step 4. Preparation of D18-4: To a solution of D18-3 (1.00 g, 4.65mmol), DMAP (57.8 mg, 0.465 mmol), and triethylamine (1.29 mL, 9.3 mmol)in dichloromethane (23.3 mL) was added di-tert-butyl dicarbonate (1.5 g,6.97 mmol) at 23° C. under and argon atmosphere. After 20 h, thereaction mixture was purified directly by silica gel chromatography(0-100% ethyl acetate/hexanes gradient) to afford D18-4. ¹H NMR (400MHz, CDCl₃) δ 4.31 (dd, J=9.4, 7.9 Hz, 1H), 3.79 (ddd, J=11.0, 8.9, 2.2Hz, 1H), 3.53-3.41 (m, 1H), 2.34-2.21 (m, 1H), 1.92 (dq, J=12.2, 9.2 Hz,1H), 1.53 (s, 9H), 0.91 (s, 9H), 0.17 (s, 3H), 0.13 (s, 3H).

Step 5. Preparation of D18-5: To a solution of D18-4 (700 mg, 2.22 mmol)in tetrahydrofuran (11.1 mL) was added pent-4-enylmagnesium bromide(Novel Chemical Solutions, 0.5 M in 2-MeTHF, 4.89 mL, 2.44 mmol) at −78°C. dropwise via syringe under an argon atmosphere. After 1 h, thereaction mixture was quench with saturated aqueous ammonium chloridesolution (50 mL) and was allowed to warm to room temperature. Theresulting mixture was extracted with ethyl acetate (2×100 mL), and thecombined organic extracts were washed with brine (100 mL), were driedover anhydrous sodium sulfate and were concentrated in vacuo. The cruderesidue was purified by silica gel chromatography (0-100% ethylacetate/hexanes gradient) to afford D18-5. ¹H NMR (400 MHz, CDCl₃) δ5.77-5.62 (m, 1H), 4.95 (d, J=15.8 Hz, 1H), 4.92 (d, J=10.2 Hz, 1H),4.26 (app t, J=8.4 Hz, 1H), 3.77-3.69 (m, 1H), 3.41 (td, J=10.4, 6.7 Hz,1H), 2.48 (t, J=7.4 Hz, 2H), 2.28-2.17 (m, 1H), 1.91-1.78 (m, 2H),1.77-1.65 (m, 1H), 1.60 (quin, J=7.3 Hz, 2H), 1.47 (s, 9H), 0.85 (s,9H), 0.11 (s, 3H), 0.07 (s, 3H).

Step 6. Preparation of D18-6: To a solution of D18-5 (740 mg, 1.92 mmol)and triethylsilane (6.10 mL, 38.4 mmol) in dichloromethane (9.6 mL) wasadded boron trifluoride diethyl etherate (308 μL, 2.50 mmol) at −78° C.dropwise via syringe under an argon atmosphere. After 1 h, the reactionmixture was allowed to warm to room temperature. After an additional 4h, the reaction was quenched with saturated aqueous ammonium chloridesolution (10 mL), and was diluted with saturated sodium bicarbonatesolution (50 mL). The resulting mixture was extracted with ethyl acetate(50 mL), and the organic layer was dried over anhydrous sodium sulfateand was concentrated in vacuo to afford crude free amine which was useddirectly in the next step. To a solution of the crude free amine, andtriethylamine (535 μL, 3.84 mmol) in tetrahydrofuran (9.6 mL) was addedacetic anhydride (146.5 μL, 1.55 mmol) at room temperature under anargon atmosphere. After 1 h, the resulting mixture was concentrated invacuo and the crude residue was purified by silica gel chromatography(0-100% ethyl acetate/hexanes gradient) to afford D18-6 (2:1diastereomeric mixture favoring desired1-((2S,3R)-3-(tert-butyldimethylsilyloxy)-2-(pent-4-enyl)pyrrolidin-1-yl)ethanonediastereomer). ¹H NMR (400 MHz, CDCl₃, Minor diastereomer denoted by *)δ 5.80-5.64 (m, 1H, 1H*), 5.01-4.82 (m, 2H, 2H*), 4.10 (d, J=4.2 Hz,1H*), 4.04 (d, J=3.7 Hz, 1H), 3.82 (dd, J=10.3, 4.0 Hz, 1H), 3.66-3.56(m, 1H*), 3.55-3.29 (m, 2H, 1H*), 3.24-3.16 (m, 1H*), 2.37-2.25 (m,1H*), 2.08-1.88 (m, 2H, 1H*), 2.03 (s, 3H*), 2.00 (s, 3H), 1.81-1.61 (m,2H, 2H*), 1.50-1.01 (m, 4H, 4H*), 0.85 (s, 9H*), 0.80 (s, 9H), 0.10 (s,3H*), 0.09 (s, 3H*), 0.00 (br s, 6H).

Step 7. Preparation of D18-7: To a solution of D18-6 (338 mg, 1.08 mmol)in tetrahydrofuran (21 mL) was added TBAF (1M in tetrahydrofuran, 21 mL,21 mmol) at 0° C. under an argon atmosphere. After 17 h, the reactionmixture was concentrated in vacuo and was directly purified by silicagel chromatography (0-100% ethyl acetate/hexanes gradient) to affordD18-7 (102 mg, 2:1 diastereomeric mixture favoring desired 11-((2S,3R)-3-hydroxy-2-(pent-4-enyl)pyrrolidin-1-yl)ethanonediastereomer). ¹H NMR (400 MHz, CDCl₃ Minor diastereomer denoted by *) δ5.84-5.70 (m, 1H, 1H*), 5.06-4.91 (m, 2H, 2H*), 4.25 (d, J=3.7 Hz, 1H*),4.20 (d, J=3.7 Hz, 1H), 3.98 (dd, J=9.2, 4.2 Hz, 1H), 3.76-3.68 (m,1H*), 3.67-3.59 (m, 1H, 1H*), 3.55-3.46 (m, 1H, 2H*), 3.02-2.94 (m, 1H),2.22-1.85 (m, 2H, 2H*), 2.10 (s, 3H*), 2.07 (s, 3H), 1.82-1.59 (m, 2H,2H*), 1.55-1.13 (m, 4H, 4H*).

Step 8. Preparation of D18-8: To a solution of D18-7 (102 mg, 0.518mmol) and pyridine (8 μL, 0.104 mmol) was added DSC (159.2 mg, 0.621mmol) at room temperature, and the resulting mixture was heated to 45°C. After 16 h, the reaction mixture was allowed to cool to roomtemperature and water (518 μL), L-tert-leucine (86.5 mg, 0.518 mmol),and K₃PO₄ (330 mg, 1.55 mmol) were sequentially added, and the resultingmixture was heated to 50° C. After 6 h, the reaction mixture was allowedto cool to room temperature and was diluted with 1N aqueous hydrochloricacid solution (10 mL). The resulting mixture was extracted withdichloromethane (2×10 mL), and the combined organic extracts were driedover anhydrous sodium sulfate and were concentrated in vacuo to affordD18-8 (2:1 diastereomeric mixture favoring the desired(S)-2-(((2S,3R)-1-acetyl-2-(pent-4-enyl)pyrrolidin-3-yloxy)carbonylamino)-3,3-dimethylbutanoicacid). ¹H NMR (400 MHz, CDCl₃, Minor diastereomer denoted by *) δ5.85-5.65 (m, 1H, 1H*), 5.39 (d, J=9.3 Hz, 1H*), 5.34 (d, J=9.2 Hz, 1H),5.07-4.87 (m, 3H, 3H*), 4.16-4.03 (m, 1H, 1H*), 3.83-3.45 (m, 3H, 3H*),2.30-1.95 (m, 8H), 2.30-1.95 (m, 2H, 3H*), 1.82-1.65 (m, 2H, 1H*), 2.11(s, 3H), 2.09 (s, 3H*), 1.58-1.13 (m, 4H, 4H*), 1.01 (br s, 9H, 9H*).

Preparation of Intermediate mixture D19.

Steps 1 and 2: Preparation of D19-1: A 1.0 M THF solution of KHMDS (10mL, 10 mmol) was diluted with THF (10 mL) under Ar and the resultingsolution was cooled to −78° C. in a CO₂:acetone bath.Bicyclo[3.1.1]heptan-2-one (1.0 g, 9.1 mmol, see: Yin, et. al. J. Org.Chem. 1985, 50, 531) was added as a solution in THF (5 mL) over 2 min,washing with additional THF (2×2.5 mL) to ensure complete transfer. Theresulting mixture was stirred for 30 min, andN-(5-Chloro-2-pyridyl)bis(trifluoromethanesulfonimide) (3.8 g, 9.7 mmol)was added as a solution in THF (10 mL) over 2 min, washing withadditional THF (2×2.5 mL). The resulting mixture was stirred for 5 minand removed from the cold bath. After stirring an additional 30 min, thereaction was diluted with Et₂O (70 mL) and 1 M aqueous HCl (50 mL). Thephases were separated, and the organic phase was washed with 1 M aqueousNaOH (2×30 mL). The combined organic phase was dried over MgSO₄,filtered and concentrated to afford a crude residue. This was filteredthrough a plug of silica with 30% EtOAc in hexanes to afford a cruderesidue of (1.24 g) that was used directly in the following step. Step2: To a solution of 3-butenal diethyl acetal (1.4 mL, 8.3 mmol) under Arcooled in an ice water bath was added a 0.5 M THF solution of9-Borabicyclo[3.3.1]nonane (15.9 mL, 7.95 mmol) over 3 min. The reactionwas stirred for 20 h, with the cold bath being allowed to expireovernight. A 3 M aqueous solution of NaOH (2.9 mL, 8.7 mmol) was thenadded, and, after stirring 20 min, the resulting solution wastransferred in its entirety to a flask containing the product from Step1 (ca. 5.16 mmol) and PdCl₂(dppf).CH₂Cl₂ (420 mg, 0.51 mmol). Theresulting mixture was heated to 60° C. After stirring 14 h, the reactionmixture was diluted with Et₂O (50 mL) and H₂O (50 mL). The phases wereseparated, and the organic phase was dried over MgSO₄, filtered, andconcentrated. Purification by silica gel chromatography (0% to 10% EtOAcin hexanes following pre-equilibration with 1% Et₃N in EtOAc) providedintermediate D19-1. ¹H NMR (300 MHz, CDCl₃) 5.36-5.28 (m, 1H), 4.59 (t,J=5.6 Hz, 1H), 3.73-3.58 (m, 2H), 3.54-3.39 (m, 2H), 2.72-2.60 (m, 1H),2.45-2.34 (m, 3H), 2.23-2.08 (m, 4H), 1.89-1.76 (m, 2H), 1.67 (dt,J=16.1, 6.9 Hz, 2H), 1.58-1.47 (m, 2H), 1.23 (t, J=7.0 Hz, 6H).

Step 3: Preparation of D19-2: A solution of olefin D19-1 (660 mg, 2.77mmol) in THF (25 mL) was cooled in an ice water bath. BH₃.Me₂S was thenadded as a 1 M solution in CH₂Cl₂ (2.9 mL, 2.9 mmol) over 1 min. Theresulting solution was stirred for 2 h in the ice water bath and wasthen allowed to warm to r.t. After stirring an additional 3 h, thereaction mixture was re-cooled in an ice water bath and was diluted with2 M aqueous NaOH (7 mL) followed by 30% aqueous H₂O₂(7 mL). Theresulting mixture was stirred an additional 16 h as the cold bath wasallowed to gradually expire. The mixture was partitioned between Et₂O(100 mL) and H₂O (50 mL), the phases were separated, and the organicphase was washed with 0.5 M aqueous NaOH (50 mL). The organic phase wasdried over MgSO₄, filtered, and concentrated to afford a crude residuethat was purified by silica gel chromatography (15% to 40% EtOAc inhexanes) to afford 570 mg of Intermediate D19-2. ¹H NMR (300 MHz, CDCl₃)δ 4.60 (t, J=5.6 Hz, 1H), 3.76-3.60 (m, 3H), 3.58-3.42 (m, 2H),2.39-2.05 (m, 4H), 1.91-1.48 (m, 9H), 1.43-1.35 (m, 1H), 1.25 (t, J=7.0Hz, 6H), 1.06-0.98 (m, 1H).

Steps 4 and 5: Preparation of D19-3: Acetal D19-2 (360 mg, 1.4 mmol) wasdissolved in THF (8 mL) and H₂O (2 mL). para-Toluenesulfonic acidmonohydrate (40 mg, 0.2 mmol) was added and the resulting solution wasstirred 16 h at r.t. The reaction was diluted with Et₂O (50 mL) and H₂O(30 mL) and the phases were separated. The aqueous phase was extractedwith Et₂O (30 mL) and the combined organic phase was washed withsaturated aqueous NaHCO₃ (15 mL). The organic phase was dried overMgSO₄, filtered, and concentrated to afford a crude residue that wasused immediately in the following step. Step 5: Methyltriphenylphosphonium bromide (1.66 g, 4.6 mmol) was suspended in THF (40mL) under Ar and was cooled via a CO₂/acetone bath to −78° C. A 1 Msolution of NaHMDS in THF (4.2 mL, 4.2 mmol) was added in dropwisefashion and the resulting yellow suspension was stirred for 5 min. Themixture was removed from the cold bath and stirring continued anadditional 30 min. The mixture was then re-cooled to −78° C. and thecrude residue from the previous step (ca. 1.4 mmol) was added as asolution in THF (5 mL) over 5 min, washing with additional THF (2×2.5mL) to ensure complete transfer. The resulting mixture was stirred for 5min and was then placed in an ice water bath and stirred an additional 1h. The reaction was quenched with saturated aqueous NH₄Cl (20 mL) andwas diluted with Et₂O (30 mL) and H₂O (20 mL). The phases were separatedand the organic phase was dried over MgSO₄, filtered, and concentratedonto 5 g silica gel. Purification by silica gel chromatography (10% to30% EtOAc in hexanes) provided D19-3. ¹H NMR (300 MHz, CDCl₃) δ6.01-5.81 (m, 1H), 5.22-5.05 (m, 2H), 3.79-3.66 (m, 1H), 2.43-2.25 (m,2H), 2.24-2.04 (m, 4H), 1.83-1.16 (m, 10H).

Step 6: Intermediate D19-3 (270 mg, 1.5 mmol) was dissolved in DMF (2.0mL). Pyridine (125 μL, 1.5 mmol) and DSC (500 mg, 1.9 mmol) were added,and the reaction was stirred at 45° C. for 15 h. The reaction was thenplaced in an ice water bath and H₂O (2.0 mL) was added dropwise over 30s. The mixture was removed from the cold bath and allowed to stir 10min. The mixture was re-cooled in an ice water bath and L-tert-leucine(259 mg, 1.97 mmol) was added followed by K₃PO₄ (835 mg, 3.93 mmol). Thereaction mixture was removed from the cold bath and allowed to stir atr.t. for 5.25 h. The mixture was then diluted with EtOAc (40 mL), 1 Maqueous HCl (20 mL), and H₂O (15 mL). The phases were separated, and theaqueous phase was extracted with EtOAc (30 mL). The combined organicphase was washed with 0.2 M aqueous HCl (2×25 mL), dried over Na₂SO₄,filtered, and concentrated to afford a mixture of diastereomers D19 (505mg) as a colorless oil. LCMS-ESI (m/z): [M+H]⁺ calcd for C₁₉H₃₂NO₄:338.2. found: 337.8.

Preparation of Intermediate E1.

Intermediate E1 (2-chloro-6-methoxy-3-(methylsulfonyl)quinoxaline) wasprepared according to Mahata, P. K., et al. Org. Lett. 2005, 7, 2169.

Preparation of Intermediate E2.

Step 1. Preparation of E2-1: In a round bottom flask,3-(benzyloxy)aniline (4.025 g, 20.20 mmol) and1,1-bis(methylthio)-2-nitroethylene (3.338 g, 20.20 mmol) in ethanol (40mL) was refluxed for 24 h with constant stirring. The reaction mixturewas then cooled in an ice bath and diluted with ether (150 mL). Themixture was filtered and washed with ether to afford E2-1 (3.32 g) as ayellow solid which was used directly in the following in step. LCMS-ESI⁺(m/z): [M+H]⁺ calcd for C₁₆H₁₇N₂O₃S: 317.1. found: 317.1.Step 2. Preparation of E2-2: To a suspension of E2-1 (3.32 g, 10.49mmol) in 25 mL MeCN, POCl₃ (2.93 mL, 31.5 mmol) was added dropwise over15 min with constant stirring. The reaction mixture was warmed to 80° C.and stirred for 5 h. The reaction was then cooled to ambient temperatureand neutralized with ice cold saturated aqueous NaHCO₃ solution,extracted three times with CH₂Cl₂ (100 mL), washed with water, brine anddried over anhydrous Na₂SO₄. The solvent was removed under reducedpressure. The crude material was eluted through a plug of silica withCH₂Cl₂. The solvent was removed under reduced pressure and the solid waswashed with MeCN to afford E2-2 (1.56 g) as an off white solid. LCMS-ESI(m/z): [M+H]⁺ calcd for C₁₆H₁₄ClN₂OS: 317.1. found: 317.3.Step 3. Preparation of Intermediate E2. A solution of mCPBA (1.87 g,10.83 mmol) in CH₂Cl₂ (40 mL) was added dropwise to a stirred solutionof E2-2 (1.56 g, 4.92 mmol) in CH₂Cl₂ (40 mL) at 0° C. over a period of30 min. The reaction mixture was further stirred at ambient temperaturefor 5 h. It was then poured into ice could saturated aqueous NaHCO₃ andpartitioned with CH₂Cl₂. The organic layer was then washed subsequentlywith water, brine and dried over anhydrous Na₂SO₄. The solvent wasremoved under reduced pressure and the crude material was purified bynormal phase chromatography with CH₂Cl₂ to provide the title compoundIntermediate E2 as a pale yellow solid. LCMS-ESI (m/z): [M+H]⁺ calcd forC₁₆H₁₄ClN₂O₃S: 349.0. found: 349.0.

Preparation of Intermediate E3.

Step 1. Preparation of E3-1: To a solution of3-bromo-3,3-difluoroprop-1-ene (25.0 g, 159 mmol) and diethyl oxalate(21.6 mL, 159 mmol) in THF (380 mL), diethyl ether (90 mL) and n-pentane(90 mL) at −100° C. was added dropwise n-butyllithium (2.5 M in hexane,67 mL, 167.6 mmol) over 30 min. The reaction mixture was stirred at −95°C. for 1 h and −78° C. for 2 h, and quenched with aq. NH₄Cl (11 g in 150mL of water). The mixture was extracted with ether (three times). Theorganic layers were washed with 1 N aqueous HCl, brine, and dried overNa₂SO₄, and concentrated to give the crude residue, which was purifiedby silica gel chromatography (EtOAc in hexanes: 0% to 40%) to give E3-1(7.0 g). ¹H NMR (300 MHz, CDCl₃) δ 5.98-6.18 (m, 1H), 5.78 (dd, J=0.9Hz, 13 Hz, 1H), 5.60 (dd, J=0.9 Hz, 11 Hz, 1H), 4.38 (q, J=6.9 Hz, 2H),1.37 (t, J=7.2 Hz, 3H).Step 2. Preparation of E3-2 and E3-3: To a solution of E3-1 (14.0 g,78.6 mmol) and 4-methoxybenzene-1,2-diamine dihydrochloride (15.08 g,71.4 mmol) in EtOH (360 mL) at rt was added triethylamine (19.9 mL,142.8 mmol). The reaction mixture was stirred at rt overnight. Themixture was concentrated. Slurrying in dichloromethane (30 mL) andfiltering gave some separation of regioisomers with E3-2 as theprecipitating species. (16.5 g total yield from filtration andsubsequent chromatography). ¹H NMR (400 MHz, CDCl₃) δ 11.940 (br s, 1H),7.850 (d, J=9 Hz, 1H), 6.985 (dd, J=3 Hz, 9 Hz, 1H), 6.754 (d, J=2 Hz,1H), 6.625-6.498 (m, 1H), 5.907 (dt, J=17, 2 Hz, 1H), 5.601 (d, J=11 Hz,1H), 3.938 (s, 3H). The mixture was slurried, filtered, and concentratedonce more, then was purified by silica gel chromatography (EtOAc inhexanes: 5% to 34%) to give E3-3 (2.07 g) as the first elutingcomponent. ¹H NMR (400 MHz, CDCl₃) δ 12.05 (br s, 1H), 7.850 (d, J=9 Hz,1H), 6.986 (dd, J=3 Hz, 9 Hz, 1H), 6.761 (d, J=3 Hz, 1H), 6.597-6.526(m, 1H), 5.91 (dt, J=17, 2 Hz, 1H), 5.601 (d, J=11 Hz, 1H), 3.939 (s,3H).Step 3. Preparation of Intermediate E3: A solution of E3-3 (2.07 g, 8.2mmol in 1 mL DMF was treated with POCl₃ (0.8 mL) and heated at 65° C.for 2.5 h. The reaction was diluted with EtOAc and quenched by pouringinto ice water. The organic phase was washed subsequently with saturatedaqueous sodium bicarbonate and brine, dried over sodium sulfate andconcentrated to give 2.1 g of Intermediate E3. ¹H NMR (400 MHz, CDCl₃) δ8.028 (d, J=10 Hz, 1H), 7.46 (dd, J=3 Hz, 9 Hz, 1H), 7.32 (d, J=3 Hz,1H), 6.549-6.478 (m, 1H), 5.86 (dt, J=17, 2 Hz, 1H), 5.67 (d, J=11 Hz,1H), 3.981 (s, 3H).

Preparation of Intermediate E4.

Intermediate E4 (2-chloro-3-(1,1-difluoroallyl)quinoxaline) was preparedin a similar fashion to Intermediate E3, substituting 1,2-diaminobenzenefor 4-methoxybenzene-1,2-diamine dihydrochloride in Step 2.

Preparation of Intermediate E5.

Intermediate E5 (2,6-dichloro-3-(methylsulfonyl)quinoxaline) wasprepared according to Mahata, P. K., et al. Org. Lett. 2005, 7, 2169.

Preparation of Intermediate E6.

Step 1. Preparation of E6-1: A 1-L 3-necked round-bottom flask wascharged with a solution of 3-bromo-3,3-difluoroprop-1-ene (25 g, 159.3mmol) in DMF (360 mL) and water (90 mL). The resulting solution wastreated with ethyl 2-oxoacetate (33 mL, 1 M in toluene), and In (25 g).The reaction mixture was stirred overnight at rt and then extracted with3×300 mL of ether. The organic layers were combined, washed with 1×100mL of saturated aqueous NH₄Cl and 1×100 mL of brine, dried overanhydrous Na₂SO₄ and concentrated in vacuo to afford E6-1 that was usedsubsequently without additional purification.Step 2. Preparation of E6-2. To hydroxyester E6-1 (58.1 g, 323 mmol) wasadded DCM (700 mL) in a 2 L 3-neck flask equipped with overhead stirringand an internal temperature probe. Then TEMPO (5.4 g, 35 mmol), buffersolution (prepared by dissolving 4.2 g NaHCO₃ and 0.53 g Na₂CO₃ per 100mL water, 700 mL, 7v), and NaOCl (Clorox 6.15% wt, 422 mL, 395 mmol)were sequentially added to the flask at 20° C. After 2 h the organiclayer was separated and the aqueous phase extracted with ethyl acetate(2×300 mL). The combined organic layers were dried over anhydrous Na₂SO₄and concentrated in vacuo to afford E6-2. ¹H-NMR (300 MHz, CDCl₃) δ5.98-6.18 (m, 1H), 5.78 (dd, J=0.9 Hz, 13 Hz, 1H), 5.60 (dd, J=0.9 Hz,11 Hz, 1H), 4.38 (q, J=6.9 Hz, 2H), 1.37 (t, J=7.2 Hz, 3H).Step 3. Preparation of E6-3. To a solution of ethyl3,3-difluoro-2,2-dihydroxypent-4-enoate E6-2 (57.4 g, 292 mmol) in THF(725 mL) and water (131 mL) was added LiOH*H₂O (22 g, 529 mmol) at 20°C. After 2.5 h, the reaction mixture was concentrated in vacuo. Thesolid residue was suspended in water (300 mL) and the resulting mixturewas acidified to pH=1 with concentrated aqueous hydrochloric acidsolution. The resulting mixture was stirred until all solids weredissolved (˜1.5 h), and then sodium chloride was added until thesolution was saturated. The resulting solution was extracted with MTBE(2×500 mL) and ethyl acetate (2×500 mL), and the combined organic layerswere dried over anhydrous Na₂SO₄ and were concentrated in vacuo. Thecrude orange solid residue was suspended into DCM (100 mL) and wasstirred until the solids were finely distributed before hexanes (75 mL)were slowly added via addition funnel. The resulting solids werecollected by vacuum filtration through a medium fritted funnel andwashed with 1:1 dichloromethane/hexanes (2×10 mL) to afford the desiredproduct. ¹H-NMR (400 MHz, DMSO-d₆) δ 13.17 (bs, 1H), 6.18-6.01 (m, 1H),5.64-5.52 (m, 2H).Step 4. Preparation of E6-4 and E6-5: A solution of E6-3 (0.5 g, 3.3mmol) in EtOH (12 mL) was treated with 3,4-diaminobenzonitrile (0.47 g,3.5 mmol). The reaction mixture was heated at 80° C. for 1 h, thenconcentrated in vacuo. The resulting residue was absorbed on silica gel,then was purified by column chromatography to give E6-4 (0.5 g) as thefirst eluting component. ¹H-NMR (400 MHz, CD₃OD) δ 8.01 (d, 1H), 7.65(dd, 2H), 6.49 (m, 1H), 5.80 (dt, 1H), 5.60 (d, 1H). E6-5 (0.2 g) wasrecovered as the second eluting component. ¹H-NMR (400 MHz, CD₃OD) δ8.25 (d, 1H), 7.87 (dd, 1H), 7.41 (d, 1H), 6.49 (m, 1H), 5.80 (dt, 1H),5.59 (d, 1H).Step 5. Preparation of Intermediate E6: A solution of E6-4 (0.5 g, 2mmol in 4.5 mL DMF was treated with POCl₃ (3 mL) and heated at 65° C.for 3 h. The reaction was diluted with EtOAc and quenched by pouringinto ice water. The organic phase was washed subsequently with saturatedaqueous NaHCO₃ and brine, dried over anhydrous Na₂SO₄ and concentratedin vacuo to give 0.48 g of Intermediate E6(3-chloro-2-(1,1-difluoroallyl)quinoxaline-6-carbonitrile). ¹H-NMR (400MHz, CD₃OD) δ 8.52 (s, 1H), 8.30 (d, 1H), 8.13 (dd, 1H), 6.55 (m, 1H),5.84 (dt, 1H), 5.72 (d, 1H).

Preparation of Intermediate E7

Step 1. Preparation of E7-1: To a solution of E3-1 (1.84 g, 10.93 mmol)and 4-(difluoromethoxy)benzene-1,2-diamine (1.90 g, 10.93 mmol, preparedaccording to Reference Example 30y of WO2003035065, p. 511.) in DMF (40mL) at rt was added DIPEA (9.5 mL, 54.65 mmol) and HATU (6.23 g, 16.4mmol). The reaction mixture was stirred at room temperature for 24 h,diluted with ethyl acetate (100 mL), washed with water (100 mL) andbrine (50 mL). The mixture was concentrated in vacuo. Purification viasilica gel chromatography (EtOAc in hexanes: 20% to 60%) provided E7-1(800 mg) as the later eluting fraction of two with the similar massspectra. LCMS-ESI (m/z): [M+H]⁺ calcd for C₁₂H₉F₄N₂O: 289.2. found:289.0.Step 2: Preparation of Intermediate E7: Hydroxyquinoxaline E7-1 (800 mg,2.8 mmol), POCl₃ (1.65 mL, 3.0 mmol) and DMF (10 mL) are combined at rtand then heated to 65° C. for 2.5 h at which time additional POCl₃ (0.2mL, 0.36 mmol) was added. The reaction was heated an additional 3 h at65° C. then cooled to rt. The reaction was quenched by addition of coldwater (30 mL), and taken up into ethyl acetate (50 mL), washed withsaturated aqueous Na₂CO₃ (100 mL) followed by brine (50 mL), and driedover anhydrous MgSO₄. The resulting solution was concentrated in vacuoto give Intermediate E7 (859 mg) which was used subsequently withoutfurther purification. LCMS-ESI (m/z): [M+H]⁺ calcd for C₁₂H₈ClF₄N₂O:307.0. found: 307.0.

Preparation of Intermediate E8.

Intermediate E8 (2-chloro-6-fluoro-3-(methylsulfonyl)quinoxaline) wasprepared according to Mahata, P. K., et al. Org. Lett. 2005, 7, 2169.

Preparation of Intermediate E9.

2,7-dichloro-3-(prop-2-en-1-yl)quinazolin-4(3H)-one (Intermediate E9)was prepared according to Step 3 of Intermediate D5 of WO '040 p 53-4.

PREPARATION OF EXAMPLES Example 1 Preparation of(1aR,5S,8S,9S,10R,22aR)-5-tert-butyl-N-[(1R,2R)-2-(difluoromethyl)-1-{[(1-methylcyclopropyl)sulfonyl]carbamoyl}cyclopropyl]-9-ethyl-14-methoxy-3,6-dioxo-1,1a,3,4,5,6,9,10,18,19,20,21,22,22a-tetradecahydro-8H-7,10-methanocyclopropa[18,19][1,10,3,6]dioxadiazacyclononadecino[11,12-b]quinoxaline-8-carboxamide

Step 1. Preparation of 1-1: A mixture containing Intermediate B4 (2.03g, 6.44 mmol), Intermediate E1 (1.6 g, 5.85 mmol), and cesium carbonate(3.15 g, 9.66 mmol) in MeCN (40 mL) was stirred vigorously at rt underan atmosphere of Ar for 16 h. The reaction was then filtered through apad of Celite and the filtrate concentrated in vacuo. The crude materialwas purified by silica gel chromatography to provide 1-1 as a whitesolid (2.5 g). LCMS-ESI⁺ (m/z): [M-Boc+2H]⁺ calcd for C₂₀H₂₇ClN₃O₄:408.9. found: 408.6.

Step 2. Preparation of 1-2: To a solution 1-1 (2.5 g, 4.92 mmol) indioxane (10 mL) was added hydrochloric acid in dioxane (4 M, 25 mL, 98.4mmol) and the reaction stirred at rt for 5 h. The crude reaction wasconcentrated in vacuo to give 1-2 as a white solid (2.49 g) that wasused in subsequently without further purification. LCMS-ESI⁺ (m/z): [M]⁺calcd for C₂₀H₂₆ClN₃O₄: 407.9. found: 407.9.

Step 3. Preparation of 1-3: To a DMF (35 mL) solution of 1-2 (2.49 g,5.61 mmol), Intermediate D1 (1.75 mg, 6.17 mmol) and DIPEA (3.9 mL,22.44 mmol) was added COMU (3.12 g, 7.29 mmol) and the reaction wasstirred at rt for 3 h. The reaction was quenched with 5% aqueous citricacid solution and extracted with EtOAc, washed subsequently with brine,dried over anhydrous MgSO₄, filtered and concentrated to produce 1-3 asan orange foam (2.31 g) that was used without further purification.LCMS-ESI (m/z): [M]⁺ calcd for C₃₅H₄₉ClN₄O₇: 673.3. found: 673.7.

Step 4. Preparation of 1-4: To a solution of 1-3 (2.31 g, 3.43 mmol),TEA (0.72 mL, 5.15 mmol) and potassium vinyltrifluoroborate (0.69 mg,5.15 mmol) in EtOH (35 mL) was added PdCl₂(dppf) (0.25 g, 0.34 mmol,Frontier Scientific). The reaction was sparged with Ar for 15 min andheated to 80° C. for 2 h. The reaction was adsorbed directly onto silicagel and purified using silica gel chromatography to give 1-4 as a yellowoil (1.95 g). LCMS-ESI (m/z): [M+H]⁺ calcd for C₃₇H₅₃N₄O₇: 665.4. found:665.3.

Step 5. Preparation of 1-5: To a solution of 1-4 (1.95 g, 2.93 mmol) inDCE (585 mL) was added Zhan 1B catalyst (0.215 g, 0.29 mmol, Strem) andthe reaction was sparged with Ar for 15 min. The reaction was heated to80° C. for 1.5 h, allowed to cool to rt and concentrated. The crudeproduct was purified by silica gel chromatography to produce 1-5 as ayellow oil (1.47 g; LCMS-ESI⁺ (m/z): [M+H]⁺ calcd for C₃₅H₄₉N₄O₇: 637.4.found: 637.3).

Step 6. Preparation of 1-6: A solution of 1-5 (0.97 g, 1.52 mmol) inEtOH (15 mL) was treated with Pd/C (10 wt % Pd, 0.162 g). The atmospherewas replaced with hydrogen and stirred at rt for 2 h. The reaction wasfiltered through Celite, the pad washed with EtOAc and concentrated togive 1-6 as a brown foamy solid (0.803 g) that was used subsequentlywithout further purification. LCMS-ESI⁺ (m/z): [M+H]⁺ calcd forC₃₅H₅₁N₄O₇: 639.4. found: 639.3.

Step 7. Preparation of 1-7: To a solution of 1-6 (0.803 g, 1.26 mmol) inDCM (10 mL) was added TFA (5 mL) and stirred at rt for 3 h. Anadditional 2 mL TFA was added and the reaction stirred for another 1.5h. The reaction was concentrated to a brown oil that was taken up inEtOAc (35 mL). The organic solution was washed with water. Afterseparation of the layers, sat. aqueous NaHCO₃ was added with stirringuntil the aqueous layer reached a pH 7-8. The layers were separatedagain and the aqueous extracted with EtOAc twice. The combined organicswere washed with 1 M aqueous citric acid, brine, dried over anhydrousMgSO₄, filtered and concentrated to produce 1-6 as a brown foamy solid(0.719 g) that was used subsequently without further purification.LCMS-ESI (m/z): [M+H]⁺ calcd for C₃₁H₄₃N₄O₇: 583.3. found: 583.4.

Step 8. Preparation of Example 1: To a solution of 1-7 (0.200 g, 0.343mmol), Intermediate A10 (0.157 g, 0.515 mmol), DMAP (0.063 g, 0.51 mmol)and DIPEA (0.3 mL, 1.72 mmol) in DMF (3 mL) was added HATU (0.235 g,0.617 mmol) and the reaction was stirred at rt o/n. The reaction wasdiluted with MeCN and purified directly by reverse phase HPLC (Gemini,30-100% MeCN/H₂O+0.1% TFA) and lyophilized to give Example 1 (118.6 mg)as a solid TFA salt. Analytic HPLC RetTime: 8.63 min. LCMS-ESI⁺ (m/z):[M+H]⁺ calcd for C₄₀H₅₅F₂N₆O₉S: 833.4. found: 833.5. ¹H NMR (400 MHz,CD₃OD) δ 9.19 (s, 1H); 7.80 (d, J=8.8 Hz, 1H); 7.23 (dd, J=8.8, 2.4 Hz,1H); 7.15 (d, J=2.4 Hz, 1H); 5.89 (d, J=3.6 Hz, 1H); 5.83 (td,J_(H-F)=55.6 Hz, J=6.4 Hz, 1H); 4.56 (d, J=7.2 Hz, 1H); 4.40 (s, 1H)4.38 (ap d, J=7.2 Hz, 1H); 4.16 (dd, J=12, 4 Hz, 1H); 3.93 (s, 3H); 3.75(dt, J=7.2, 4 Hz, 1H); 3.00-2.91 (m, 1H); 2.81 (td, J=12, 4.4 Hz, 1H);2.63-2.54 (m, 1H); 2.01 (br s, 2H); 1.88-1.64 (m, 3H); 1.66-1.33 (m,11H) 1.52 (s, 3H); 1.24 (t, J=7.2 Hz, 3H); 1.10 (s, 9H); 1.02-0.96 (m,2H); 0.96-0.88 (m, 2H); 0.78-0.68 (m, 1H); 0.55-0.46 (m, 1H).

Example 2 Preparation of(1aR,5S,8S,9S,10R,22aR)-5-tert-butyl-N-[(1R,2R)-1-[(cyclopropylsulfonyl)carbamoyl]-2-(difluoromethyl)cyclopropyl]-9-ethyl-14-methoxy-3,6-dioxo-1,1a,3,4,5,6,9,10,18,19,20,21,22,22a-tetradecahydro-8H-7,10-methanocyclopropa[18,19][1,10,3,6]dioxadiazacyclononadecino[11,12-b]quinoxaline-8-carboxamide

Example 2 was prepared in a similar fashion to Example 1, substitutingIntermediate A9 for Intermediate A10 in Step 8. Example 2 was isolated(37.9 mg) in approximately 85% purity as a TFA salt. Analytic HPLCRetTime: 8.54 min. LCMS-ESI⁺ (m/z): [M+H]⁺ calcd for C₃₉H₅₃F₂N₆O₉S:819.35. found: 819.51. ¹H NMR (400 MHz, CDCl₃) δ 10.26 (s, 1H); 7.90 (d,J=9.2 Hz, 1H); 7.26 (dd, J=9.2, 2.4 Hz, 1H); 7.10 (d, J=2.4 Hz, 1H);6.68 (br s, 1H); 6.01 (td, J_(H-F)=55.6 Hz, J=6.8 Hz, 1H); 5.87 (d,J=3.6 Hz, 1H); 5.38, (d, J=10 Hz, 1H); 4.50-4.40 (m, 3H); 4.10 (dd,J=12, 3.6 Hz, 1H); 3.95 (s, 3H); 3.79-3.72 (m, 1H); 2.96-2.82 (m, 3H);2.63-2.56 (m, 1H); 2.14 (t, J=6.8 Hz, 1H); 1.98-1.86 (m, 1H); 1.84-1.28(m, 13H); 1.23 (t, J=7.2 Hz, 3H); 1.16-0.92 (m, 3H); 1.09 (s, 9H);0.74-0.64 (m, 1H); 0.48 (q, J=6.4 Hz, 1H).

Example 3 Preparation of(1aR,5S,8S,9S,10R,22aR)-5-tert-butyl-N-{(1R,2R)-1-[(cyclopropylsulfonyl)carbamoyl]-2-ethylcyclopropyl}-9-ethyl-14-methoxy-3,6-dioxo-1,1a,3,4,5,6,9,10,18,19,20,21,22,22a-tetradecahydro-8H-7,10-methanocyclopropa[18,19][1,10,3,6]dioxadiazacyclononadecino[11,12-b]quinoxaline-8-carboxamide

Example 3 was prepared in a similar fashion to Example 1, substitutingIntermediate A3 for Intermediate A10 in Step 8. Example 3 was isolated(0.035 g) in approximately 88% purity as a TFA salt. Analytic HPLCRetTime: 8.63 min. LCMS-ESI⁺ (m/z): [M+H]⁺ calcd for C₄₀H₅₇N₆O₉S: 797.4.found: 797.5. ¹H NMR (400 MHz, CD₃OD) δ 8.98 (s, 1H); 7.80 (d, J=9.2 Hz,1H); 7.23 (d, J=9.2, 2.8 Hz, 1H); 7.15 (d, J=2.8 Hz, 1H); 5.89 (d, J=3.6Hz, 1H); 4.58 (d, J=7.6 Hz, 1H); 4.41-4.32 (m, 2H); 4.16 (dd, J=12.4 Hz,3.6 Hz, 1H); 3.93 (s, 3H); 3.74 (dt, J=6.8, 2.8 Hz, 1H); 3.20-2.91 (m,2H); 2.86-2.76 (m, 1H); 2.61-2.53 (m, 1H); 1.88-1.68 (m, 4H); 1.66-1.34(m, 9H); 1.34-1.20 (m, 5H); 1.18-1.04 (m, 3H); 1.10 (s, 9H); 1.00-0.92(m, 7H); 0.79-0.69 (m, 1H); 0.50 (br d, J=7.2 Hz, 1H).

Example 4 Preparation of (1aR,5S,8S,9S,10R,22aR)-5-tert-butyl-9-ethyl-N-[(1R,2R)-2-ethyl-1-{[(1-methylcyclopropyl)sulfonyl]carbamoyl}cyclopropyl]-14-methoxy-3,6-dioxo-1,1a,3,4,5,6,9,10,18,19,20,21,22,22a-tetradecahydro-8H-7,10-methanocyclopropa[18,19][1,10,3,6]dioxadiazacyclononadecino[11,12-b]quinoxaline-8-carboxamide

Example 4 was prepared in a similar fashion to Example 1, substitutingIntermediate A4 for Intermediate A10 in Step 8. Example 4 was isolated(0.018 g) in approximately 88% purity as a TFA salt. Analytic HPLCRetTime: 8.75. LCMS-ESI (m/z): [M+H]⁺ calcd for C₄₁H₅₉N₆O₉S: 811.4.found: 811.6. ¹H NMR (400 MHz, CD₃OD) δ 8.91 (s, 1H); 7.80 (d, J=9.2 Hz,1H); 7.23 (dd, J=9.2, 2.8 Hz, 1H); 7.16 (d, J=2.8 Hz, 1H); 5.90 (d,J=3.6 Hz, 1H); 4.59 (d, J=6.8 Hz, 1H); 4.38 (s, 1H); 4.37 (d, J=11.6 Hz,1H), 4.16 (dd, J=11.6, 6.8 Hz, 1H), 3.93 (s, 3H); 3.74 (dt, J=6.8, 3.6Hz, 1H); 3.10-2.91 (m, 1H); 2.90-2.7 (m, 1H); 2.63-2.55 (m, 1H);1.86-1.69 (m, 3H); 1.65-1.36 (m, 13H), 1.52 (s, 3H); 1.24 (t, J=7.2 Hz,3H); 1.16-1.06 (m, 2H); 1.10 (s, 9H); 1.02-0.85 (m, 7H); 0.79-0.68 (m,1H); 0.50 (br d, J=6.8 Hz, 1H).

Example 5 Preparation of(3aR,7S,10S,11S,12R,24aR)-7-tert-butyl-N-[(1R,2R)-1-[(cyclopropylsulfonyl)carbamoyl]-2-(difluoromethyl)cyclopropyl]-11-ethyl-16-methoxy-5,8-dioxo-1,2,3,3a,5,6,7,8,11,12,20,21,22,23,24,24a-hexadecahydro-1OH-9,12-methanocyclopenta[18,19][1,10,3,6]dioxadiazacyclononadecino[11,12-b]quinoxaline-10-carboxamide

Step 1. Preparation of 5-1: HATU (555 mg, 1.46 mmol, Oakwood) and DIPEA(1.10 mL, 6.35 mmol) were added to a mixture of 1-2 (533 mg, 1.20 mmol)and Intermediate D5 (414 mg, 1.33 mmol) in 12 mL of DMF under argon.After stirring overnight, the reaction mixture was poured into water andextracted three times with ethyl acetate. Combined organics were washedwith water and brine, dried (MgSO₄), filtered, and concentrated underreduced pressure. The resulting residue was purified by silica gelchromatography (0-35% ethyl acetate in hexanes) to yield 5-1 (713 mg) asa white solid. LCMS-ESI (m/z): [M+H]⁺ calcd for C₃₇H₅₄ClN₄O₇: 701.36.found: 701.58.

Step 2. Preparation of 5-2: Pd(dppf)Cl₂*CH₂Cl₂ (94 mg, 0.115 mmol,Strem) was added to a deoxygenated mixture of 5-1 (710 mg, 1.01 mmol),potassium vinyltrifluoroborate (213 mg, 1.59 mmol), and triethylamine(0.210 mL, 1.52 mmol) in 11 mL of EtOH at room temperature. Reactionmixture was heated at 78° C. under argon for one hour. After cooling toroom temperature, reaction mixture was poured into water and extractedthree times with ethyl acetate. Combined organics were washed with waterand brine, dried (MgSO₄), filtered, and concentrated under reducedpressure to yield 5-2 (699 mg), which was used in the next step withoutfurther purification. LCMS-ESI (m/z): [M+H]⁺ calcd for C₃₉H₅₇N₄O₇:693.41. found: 693.47.

Step 3. Preparation of 5-3: A mixture of 5-2 (699 mg, 1.01 mmol) andZhan 1B catalyst (81 mg, 0.111 mmol, Strem) in 200 mL of DCE wasdeoxygenated under argon for 25 minutes. The mixture was then heated at95° C. for 45 minutes. Reaction mixture was heated at 95° C. for 10additional minutes, was cooled to room temperature, and thenconcentrated under reduced pressure. The resulting residue was purifiedby silica gel chromatography (0-30% ethyl acetate in hexanes) to yield5-3 (336 mg) as a light brown solid. LCMS-ESI (m/z): [M+H]⁺ calcd forC₃₇H₅₃N₄O₇: 665.38. found: 665.53.

Step 4. Preparation of 5-4: Palladium on carbon (10 wt. % Pd, 102 mg,0.096 mmol) was added to a solution of 5-3 (330 mg, 0.497 mmol) in 8 mLof ethanol and 3.5 mL of ethyl acetate. Mixture was stirred under anatmosphere of hydrogen for 100 minutes and was then filtered overCelite, washing with ethyl acetate. Filtrate was concentrated underreduced pressure to yield 5-4 (64 mg) as a light yellow-brown solidfilm, which was used in the next step without further purification.LCMS-ESI (m/z): [M+H]⁺ calcd for C₃₇H₅₅N₄O₇: 667.40. found: 667.52.

Step 5. Preparation of 5-5: TMSOTf (0.53 mL, 2.91 mmol) was addeddropwise to a solution of 5-4 (329 mg, 0.494 mmol) in 10 mL ofdichloromethane under argon at room temperature. After one hour, anadditional 0.3 mL of TMSOTf was added. After an additional hour,reaction mixture was concentrated under reduced pressure. The resultingfilm was taken up in 12 mL of toluene and concentrated under reducedpressure. This process was repeated a second time to yield 5-5 (301 mg),which was used in the next step without further purification. LCMS-ESI(m/z): [M+H]⁺ calcd for C₃₃H₄₇N₄O₇: 611.34. found: 611.46.

Step 6. Preparation of Example 5: HATU (129 mg, 0.339 mmol) and DIPEA(0.22 mL, 1.27 mmol) were added to a mixture of 5-5 (134 mg, 0.22 mmol)and Intermediate A9 (95 mg, 0.328 mmol) in 6.6 mL of MeCN under argon.After stirring for 5 h, reaction mixture was poured into water andextracted three times with ethyl acetate. Combined organics were washedwith water and brine, dried (MgSO₄), filtered, and concentrated underreduced pressure. The resulting residue was purified by reverse phasepreparatory HPLC (15-100% acetonitrile in water, with 0.1%trifluoroacetic acid buffer) to yield Example 5 (43 mg) as a lightyellow solid, trifluoroacetic acid salt, after lyophilization. AnalyticHPLC RetTime: 9.11 min. LCMS-ESI⁺ (m/z): [M+H]⁺ calcd for C₄₁H₅₇F₂N₆O₉S:847.38. found: 847.62. ¹H NMR (400 MHz, CD₃OD): δ 9.31 (s, 1H), 7.80 (d,J=9.2 Hz, 1H), 7.23 (dd, J=15.4, 2.8 Hz, 1H), 7.19 (d, J=2.8 Hz, 1H),5.87 (td, J_(H-F)=56 Hz, J=6 Hz, 1H), 5.87-5.83 (m, 1H), 4.59 (d, J=7.6Hz, 1H), 4.38 (s, 1H), 4.23-4.14 (m, 2H), 3.93 (s, 3H), 3.06-2.94 (m,2H), 2.77-2.67 (m, 1H), 2.65-2.58 (m, 1H), 2.07-2.01 (m, 2H), 1.98-1.74(m, 4H), 1.72-1.52 (m, 4H), 1.50-1.20 (m, 12H), 1.18-1.02 (m, 8H), 1.06(s, 9H).

Example 6 Preparation of(3aR,7S,10S,11S,12R,24aR)-7-tert-butyl-N-[(1R,2R)-2-(difluoromethyl)-1-{[(1-methylcyclopropyl)sulfonyl]carbamoyl}cyclopropyl]-1-ethyl-16-methoxy-5,8-dioxo-1,2,3,3a,5,6,7,8,11,12,20,21,22,23,24,24a-hexadecahydro-10H-9,12-methanocyclopenta[18,19][1,10,3,6]dioxadiazacyclononadecino[11,12-b]quinoxaline-10-carboxamide

Example 6 was prepared in a similar fashion to Example 5, substitutingIntermediate A10 for Intermediate A9 in Step 6. Example 6 was isolated(29 mg) as a white solid. Analytic HPLC RetTime: 9.26 min. LCMS-ESI(m/z): [M+H]⁺ calcd for C₄₂H₅₉F₂N₆O₉S: 861.40. found: 861.20. ¹H NMR(400 MHz, CDCl₃) b 9.91 (s, 1H), 7.82 (d, J=12 Hz, 1H), 7.18 (d, J=12 Hz1H), 7.13-7.06 (m, 1H), 6.48 (s, 1H), 5.95 (td, J_(H-F)=56 Hz, J=6 Hz,1H), 5.82 (d, J=4.4 Hz, 1H), 5.33 (d, J=10 Hz, 1H), 4.95-4.91 (m, 1H),4.38-4.31 (m, 2H), 4.10-3.88 (m, 2H), 3.98 (s, 3H), 2.98-2.89 (m, 1H),2.67-2.59 (m, 1H), 2.05-1.65 (m, 4H), 1.64-1.21 (m, 12H), 1.40 (s, 3H),1.17-0.80 (m, 12H), 1.09 (s, 9H).

Example 7 Preparation of(1aR,5S,8S,9S,10R,22aR)-5-tert-butyl-N-[(1R,2R)-2-(difluoromethyl)-1-{[(1-methylcyclopropyl)sulfonyl]carbamoyl}cyclopropyl]-9-ethyl-14-methoxy-1a-methyl-3,6-dioxo-1,1a,3,4,5,6,9,10,18,19,20,21,22,22a-tetradecahydro-8H-7,10-methanocyclopropa[18,19][1,10,3,6]dioxadiazacyclononadecino[11,12-b]quinoxaline-8-carboxamide

Step 1. Preparation of 1-2 (free base): Carbamate 1-1 (350 mg, 0.689mmol) was added to a flask containing a 4:1 mixture of t-butylacetate:DCM (3.5 mL). To this solution was then added methanesulfonicacid (447 μL, 6.89 mmol). The reaction mixture was allowed to stir for20 min at rt, then diluted with methylene chloride (20 mL) and saturatedaqueous sodium bicarbonate (20 mL). The solution was allowed to stiruntil evolution of gas ceased, then the organics were removed and theaqueous layer was extracted twice with methylene chloride (20 mL). Thecombined organics were then washed with brine, dried over Na₂SO₄,filtered, and concentrated in vacuo. The resulting white solid 1-2 (freebase, 280 mg) was used in the subsequent reaction without furtherpurification. LCMS-ESI (m/z): [M+H]⁺ calcd for C₂₀H₂₇ClN₃O₄: 408.2.found: 408.1.

Step 2. Preparation of mixture 7-1: Amine 1-2 (281 mg, 0.689 mmol) wascombined with diastereomeric Intermediate mixture D6 (266 mg, 0.895mmol), DIPEA (600 μL, 3.45 mmol) and DMF (2 mL). HATU (340 mg, 0.895mmol) was then added to the reaction mixture, which was stirred at 40°C. for 5 h. Reaction mixture was then diluted with water (10 mL) andtaken up into methylene chloride (10 mL). Organics were separated andaqueous layer was extracted once with methylene chloride (10 mL).Combined organics were then washed with brine, dried over MgSO₄,filtered, and concentrated in vacuo. Crude residue was then purified viasilica gel chromatography to give 7-1 as a 1:1 diastereomeric mixture(280 mg). LCMS-ESI (m/z): [M+H]⁺ calcd for C₃₆H₅₂ClN₄O₇: 687.4. found:687.3.

Step 3. Preparation of 7-2: Pd(dppf)Cl₂ (29 mg, 0.0407 mmol) was addedto a degassed mixture of 7-1 (280 mg, 0.407 mmol), potassiumvinyltrifluoroborate (55 mg, 0.733 mmol), and triethylamine (91 μL,0.651 mmol) in 2 mL of ethanol at room temperature. Reaction mixture washeated at 80° C. under N₂ for one hour. After cooling to roomtemperature, reaction mixture was diluted with toluene (10 mL),concentrated in vacuo to a small volume of solvent, and rediluted intoluene (1 mL). Mixture was then loaded directly onto a silica columnand purified by silica gel chromatography to afford 7-2 as a 1:1diastereomeric mixture which was carried on to the next step withoutconcentrating fully to dryness. LCMS-ESI (m/z): [M+H]⁺ calcd forC₃₈H₅₅N₄O₇: 679.4. found: 679.4.

Step 4. Preparation of 7-3 and 7-4: Diastereomeric mixture 7-2 (276 mg,0.407 mmol) and Zhan 1B catalyst (32 mg, 0.0407 mmol, Strem) weredissolved in 80 mL of DCE and degassed under N₂ for 25 minutes. Themixture was then heated to 100° C. for 1 h. Reaction was then cooled toroom temperature and concentrated in vacuo. The resulting residue waspurified via silica gel chromatography (0% to 30% ethyl acetate inhexanes) to yield single diastereomers 7-3 (20 mg, early elutingfraction) and 7-4 (25 mg, late eluting fraction) as light brownresidues. Early eluting fraction: LCMS-ESI (m/z): [M+H]⁺ calcd forC₃₆H₅₁N₄O₇: 651.4. found: 651.3. Late eluting fraction: LCMS-ESI (m/z):[M+H]⁺ calcd for C₃₆H₅₁N₄O₇: 651.4. found: 651.3.

Step 5. Preparation of 7-5: Palladium on carbon (10% w/w, 25 mg) wasadded to a solution of 7-3 (20 mg, 0.0307 mmol) in a 1:1 mixture ofethyl acetate and dioxane (2 mL). Mixture was stirred under anatmosphere of hydrogen for 30 min and was then filtered through a plugof Celite, and washed with ethyl acetate. Filtrate was concentratedunder reduced pressure to yield 7-5 (16 mg) as a light brown film, whichwas used in the next step without further purification. LCMS-ESI⁺ (m/z):[M+H]⁺ calcd for C₃₆H₅₃N₄O₇: 653.4. found: 653.4.

Step 6. Preparation of 7-6: Intermediate 7-5 (16 mg, 0.023 mmol) wasdissolved in 2 M HCl in dioxane (2 mL) and heated at 80° C. for 1.5 hvia microwave reactor. Reaction mixture was then concentrated in vacuoto give 7-6 (15 mg) as a brown residue, which was used in the subsequentstep without further purification. LCMS-ESI⁺ (m/z): [M+H]⁺ calcd forC₃₂H₄₄N₄O₇: 597.3. found: 597.3.

Step 7. Preparation of Example 7: HATU (11.9 mg, 0.031 mmol) and DIPEA(22 μL, 0.126 mmol) were added to a mixture of 7-6 (15 mg, 0.025 mmol)and A10 (11.5 mg, 0.0377 mmol) in 1 mL of DMF. After stirring overnightat room temperature, reaction mixture was poured into water, acidifiedto pH 1 with 1 N aqueous HCl, and extracted three times with methylenechloride (15 mL). Combined organics were washed with water, brine, driedover MgSO₄, filtered, and concentrated under reduced pressure. Theresulting residue was purified by reverse phase prep HPLC (5-100%acetonitrile in water, with 0.1% trifluoroacetic acid buffer) followedby silica gel chromatography to afford Example 7 (4.3 mg) as a whitesolid film. Analytic HPLC RetTime: 9.07 min. LCMS-ESI⁺ (m/z): [M+H]⁺calcd for C₄₁H₅₇F₂N₆O₉S: 847.4. found: 847.4. ¹H NMR (400 MHz, CDCl₃)(9.88 (s, 1H), 7.83 (d, J=9.1 Hz, 1H), 7.20 (dd, J=9.1 Hz, 2.8 Hz, 1H),7.07 (d, J=2.7 Hz, 1H), 6.56 (s, 1H), 5.98 (td, J_(H-F)=55.7, J=6.7 Hz,1H), 5.95 (d, J=9.6, 1H), 5.32 (d, J=9.6 Hz, 1H), 4.45 (dd, J=13.0 Hz,9.6 Hz, 2H), 4.32 (d, J=9.7 Hz, 1H), 4.13 (dd, J=15.5 Hz, 8.8 Hz, 1H),3.93 (s, 3H), 2.99-2.84 (m, 1H), 2.82-2.68 (m, 1H), 2.62-2.47 (m 1H),2.16-2.02 (m, 1H) 2.00-1.85 (m, 1H) 1.84-1.69 (m, 1H), 1.70-1.15 (m,11H), 1.52 (s, 3H), 1.50 (s, 3H), 1.20 (t, J=7.3 Hz, 3H), 1.14-0.77 (m,5H) 1.09 (s, 9H), 0.11 (m, 1H).

Example 8 Preparation of(1aS,5S,8S,9S,10R,22aS)-5-tert-butyl-N-[(1R,2R)-2-(difluoromethyl)-1-{[(1-methylcyclopropyl)sulfonyl]carbamoyl}cyclopropyl]-9-ethyl-14-methoxy-1a-methyl-3,6-dioxo-1,1a,3,4,5,6,9,10,18,19,20,21,22,22a-tetradecahydro-8H-7,10-methanocyclopropa[18,19][1,10,3,6]dioxadiazacyclononadecino[11,12-b]quinoxaline-8-carboxamide

Example 8 was prepared in a similar fashion to Example 7, substitutinglate eluting 7-4 for early eluting 7-3 in Step 5. Example 7 was isolated(2.9 mg) as a white solid. Analytic HPLC RetTime: 9.09 min. LCMS-ESI(m/z): [M+H]⁺ calcd for C₄₁H₅₇F₂N₆O₉S: 847.4. found: 847.4.

Examples 9 and 10 Preparation of(7S,10S,11S,12R)-7-tert-butyl-N-[(1R,2R)-2-(difluoromethyl)-1-{[(1-methylcyclopropyl)sulfonyl]carbamoyl}cyclopropyl]-11-ethyl-16-methoxy-5,8-dioxo-3aR-(trifluoromethyl)-1,2,3,3a,5,6,7,8,11,12,20,21,22,23,24,24a-hexadecahydro-10H-9,12-methanocyclopenta[18,19][1,10,3,6]dioxadiazacyclononadecino[11,12-b]quinoxaline-10-carboxamideand(7S,10S,11S,12R)-7-tert-butyl-N-[(1R,2R)-2-(difluoromethyl)-1-{[(1-methylcyclopropyl)sulfonyl]carbamoyl}cyclopropyl]-11-ethyl-16-methoxy-5,8-dioxo-3aS-(trifluoromethyl)-1,2,3,3a,5,6,7,8,11,12,20,21,22,23,24,24a-hexadecahydro-10H-9,12-methanocyclopenta[18,19][1,10,3,6]dioxadiazacyclononadecino[11,12-b]quinoxaline-10-carboxamide

Step 1. Preparation of 9-1: To a solution of Intermediate D8 (322 mg,0.85 mmol) and 1-2 (316 mg, 0.78 mmol) in MeCN (3.9 mL) was added HATU(323 mg, 0.85 mmol) followed by DIPEA (678 μL, 3.90 mmol) at rt under anargon atmosphere. After 2 h, the reaction mixture was concentrated invacuo, and the crude residue was purified by silica gel chromatography(0-100% ethyl acetate/hexanes gradient) to afford amide 9-1 (476 mg, 1:1diastereomeric mixture) as a colorless oil. LCMS-ESI (m/z): [M+H]⁺ calcdfor C₃₈H₅₃ClF₃N₄O₇: 769.4. found: 769.5.

Step 2. Preparation of 9-2: To a solution of 9-1 (470 mg, 612 μmol), TEA(128 μL, 918 μmol), and potassium vinyltrifluoroborate (123 mg, 918μmol) in EtOH (3.06 mL) was added PdCl2(dppf) (50 mg, 61 μmol). Thereaction mixture was deoxygenated with argon for 10 min and heated to78° C. After 1 h, the reaction mixture was allowed to cool to rt and wasconcentrated in vacuo. The crude residue was purified by silica gelchromatography (0-100% ethyl acetate/hexanes gradient) to afford vinylquinoxaline 9-2 (329 mg, 1:1 diastereomeric mixture) as a yellow oil.LCMS-ESI (m/z): [M+H]⁺ calcd for C₄₀H₅₆F₃N₄O₇: 761.4. found: 761.6.

Step 3. Preparation of 9-3: To a solution of 9-2 (329 mg, 485 μmol) inDCE (97 mL) was added Zhan 1B catalyst (35 mg, 49 μmol, Strem) and thereaction mixture was deoxygenated for 10 minutes with argon. Thereaction mixture was then heated to 100° C. After 30 min, the reactionmixture was allowed to cool to rt and was concentrated in vacuo. Thecrude residue was purified by silica gel chromatography (0-100% ethylacetate/hexanes gradient) to afford macrocycle 9-3 (301 mg, 7:4diastereomeric mixtures) as a light yellow oil. LCMS-ESI⁺ (m/z): [M+H]⁺calcd for C₃₈H₅₂F₃N₄O₇: 733.4. found: 733.5.

Step 4. Preparation of 9-4: To a solution of 9-3 (300 mg, 410 μmol) inethanol (2.00 mL) was added Pd/C (10 wt % Pd, 43 mg, 41 μmol) at rtunder an argon atmosphere. The atmosphere of the reaction was replacedwith hydrogen gas and the reaction mixture stirred vigorously at rt.After 30 min, the reaction mixture was diluted with ethyl acetate (10mL) and filtered through a pad of Celite with ethyl acetate washings(3×5 mL). The filtrate was concentrated in vacuo to afford macrocycle9-4 (295 mg, 7:4 diastereomeric mixture), which was used directly in thenext step without further purification. LCMS-ESI (m/z): [M+H]⁺ calcd forC₃₈H₅₄F₃N₄O₇: 735.4. found: 735.5.

Step 5. Preparation of 9-5: To a solution of 9-4 (295 mg, 401 μmol) inDCM (2 mL) was added TMSOTf (72.6 μL, 401 mmol) at rt under an argonatmosphere. After 1.5 h, additional TMSOTf (362.9 μL, 2.00 mmol) wasadded. After 1 h, additional TMSOTf (362.9 μL, 2.00 mmol) was added.After 2 h, the reaction mixture was added slowly to a 0.25 N aqueousNaOH solution (precooled to 0° C., 3 mL). The resulting mixture wasdiluted with 1 N aqueous HCl solution (5 mL), and was extracted with DCM(3×5 mL). The combined organic extracts were dried over anhydrous sodiumsulfate and were concentrated to afford carboxylic acid 9-5 (353 mg, 7:4diastereomeric mixture) as a tan solid, which was used directly in thenext step without further purification. LCMS-ESI⁺ (m/z): [M+H]⁺ calcdfor C₃₄H₄₅F₃N₄O₇: 679.3. found: 679.5.

Step 6. Preparation of Example 9 and Example 10: To a solution of acid9-5 (150 mg, 220 μmol) and Intermediate A10 (101 mg, 330 μmol) in MeCN(1.1 mL) was added HATU (127 mg, 330 μmol) followed by DIPEA (191 μL,1.10 mmol) at rt under an argon atmosphere. After 1 h, the reactionmixture was concentrated in vacuo, and the crude residue was purified bysilica gel chromatography (0-100% ethyl acetate/hexanes gradient). Thefractions containing the desired product were combined and wererepurified by silica gel chromatography (0-50% acetone/hexanes gradient)to afford the first eluting

Example 9 (40 mg) as a white powder and the second eluting Example 10(70 mg) as a white powder. First eluting Example 9: Analytic HPLCRetTime: 9.42 min. LCMS-ESI (m/z): [M+H]⁺ calcd for C₄₃H₅₈F₅N₆O₉S:929.4. found: 929.5. ¹H NMR (400 MHz, CDCl₃) δ 9.83 (s, 1H), 7.92 (d,J=9.1 Hz, 1H), 7.19 (dd, J=9.0, 2.6 Hz, 1H), 7.13 (d, J=2.6 Hz, 1H),5.99 (br s, 1H), 5.96 (td, J_(H-F) 55.5, J=6.6 Hz, 1H), 5.70 (d, J=10.0Hz, 1H), 4.63 (d, J=6.6 Hz, 1H), 4.38 (d, J=10.0 Hz, 1H), 4.22-4.04 (m,2H), 3.96 (s, 3H), 3.12-2.89 (m, 1H), 2.71-2.51 (m, 2H), 2.17 (s, 3H),2.15-1.82 (m, 4H), 1.83-1.34 (m, 8H), 1.36-0.98 (m, 12H), 1.26 (s, 9H),0.92-0.79 (m, 4H). Second eluting Example 10: Analytic HPLC RetTime:9.55 min. LCMS-ESI (m/z): [M+H]⁺ calcd for C₄₃H₅₈F₅N₆O₉S: 929.4. found:929.5. ¹H NMR (400 MHz, CDCl₃) δ 9.61 (s, 1H), 7.91 (d, J=9.1 Hz, 1H),7.23 (dd, J=9.0, 3.0 Hz, 1H), 7.18 (d, J=2.7 Hz, 1H), 5.98-5.91 (m, 1H),5.83 (td, J_(H-F) 55.5, J=6.6 Hz, 1H), 5.33 (d, J=9.8 Hz, 1H), 4.72-4.63(m, 1H), 4.46-4.38 (m, 1H), 4.32 (d, J=10.0 Hz, 1H), 4.25-4.14 (m, 1H),3.97 (s, 3H), 3.73 (br d, J=7.6 Hz, 1H), 3.23-3.07 (m, 1H), 2.86-2.37(m, 2H), 2.14-1.79 (m, 2H), 1.78-1.38 (m, 8H), 1.51 (s, 3H), 1.35-1.08(m, 8H), 1.25 (s, 9H), 1.05 (br s, 3H), 0.93-0.68 (m, 6H).

Examples 11 and 12 Preparation of(7S,10S,11S,12R)-7-tert-butyl-N-[(1R,2R)-1-[(cyclopropylsulfonyl)carbamoyl]-2-(difluoromethyl)cyclopropyl]-11-ethyl-16-methoxy-5,8-dioxo-3aR-(trifluoromethyl)-1,2,3,3a,5,6,7,8,11,12,20,21,22,23,24,24a-hexadecahydro-1OH-9,12-methanocyclopenta[18,19][1,10,3,6]dioxadiazacyclononadecino[11,12-b]quinoxaline-10-carboxamideand(7S,10S,11S,12R)-7-tert-butyl-N-[(1R,2R)-1-[(cyclopropylsulfonyl)carbamoyl]-2-(difluoromethyl)cyclopropyl]-11-ethyl-16-methoxy-5,8-dioxo-3aS-(trifluoromethyl)-1,2,3,3a,5,6,7,8,11,12,20,21,22,23,24,24a-hexadecahydro-1OH-9,12-methanocyclopenta[18,19][1,10,3,6]dioxadiazacyclononadecino[11,12-b]quinoxaline-10-carboxamide

Preparation of Example 11 and Example 12: To a solution of acid 9-5 (150mg, 220 μmol) and Intermediate A9 (96 mg, 330 μmol) in MeCN (1.1 mL) wasadded HATU (127 mg, 330 μmol) followed by DIPEA (191 μL, 1.10 mmol) atrt under an argon atmosphere. After 1 h, the reaction mixture wasconcentrated in vacuo, and the crude residue was purified by silica gelchromatography (0-50% acetone/hexanes gradient). The fractionscontaining the desired product were combined and were repurified bysilica gel chromatography (0-50% acetone/hexanes gradient) to afford thefirst eluting Example 11 (29 mg) as a white powder and the secondeluting Example 12 (60.2 mg) as a white powder. First eluting Example11: Analytic HPLC RetTime: 9.44 min. LCMS-ESI (m/z): [M+H]⁺ calcdC₄₂H₅₆F₅N₆O₉S: 915.4. found: 915.6. ¹H NMR (400 MHz, CDCl₃) b 10.17 (brs, 1H), 7.83 (d, J=9.1 Hz, 1H), 7.21 (dd, J=9.1, 2.7 Hz, 1H), 7.17-7.07(m, 1H), 5.99 (br s, 1H), 5.97 (td, J_(H-F) 55.5, J=6.6 Hz, 1H), 5.82(d, J=9.8 Hz, 1H), 4.55 (d, J=7.2 Hz, 1H), 4.39 (d, J=10.0 Hz, 1H),4.20-4.03 (m, 2H), 3.95 (s, J=5.9 Hz, 3H), 2.97-2.82 (m, 2H), 2.79-2.49(m, 3H), 2.24-1.81 (m, 8H), 1.80-1.11 (m, 12H), 1.10-0.98 (m, 4H), 1.07(s, 9H), 0.95-0.81 (m, 3H). Second eluting Example 12: Analytic HPLCRetTime: 9.48 min. LCMS-ESI (m/z): [M+H]⁺ calcd C₄₂H₅₆F₅N₆O₉S: 915.4.found: 915.6. ¹H NMR (400 MHz, CDCl₃) δ 10.07 (s, 1H), 7.93 (d, J=9.6Hz, 1H), 7.28-7.20 (m, 1H), 7.16 (s, 1H), 6.17-5.68 (m, 3H), 4.67-4.55(m, 1H), 4.37-4.23 (m, 2H), 4.17-4.05 (m, 1H), 3.97 (s, 3H), 3.75-3.66(m, 1H), 3.22-3.04 (m, 1H), 3.02-2.31 (m, 6H), 2.30-1.83 (m, 10H),1.85-1.13 (m, 13H), 1.06 (s, 9H), 0.95-0.79 (m, 1H).

Example 13 Preparation of(1R,4S,4aR,8S,11S,12S,13R,25aR)-8-tert-butyl-N-[(1R,2R)-1-[(cyclopropylsulfonyl)carbamoyl]-2-(difluoromethyl)cyclopropyl]-12-ethyl-17-methoxy-6,9-dioxo-2,3,4,4a,6,7,8,9,12,13,21,22,23,24,25,25a-hexadecahydro-1H,11H-1,4:10,13-dimethanoquinoxalino[2,3-k][1,10,3,6]benzodioxadiazacyclononadecine-11-carboxamide

Step 1. Preparation of diastereomer mixture 13-1 and 13-2: To a solutionof 1-2 (354 mg, 0.87 mmol), Intermediate mixture D9 and D10 (323 mg,0.96 mmol) and BEP (263 mg, 0.96 mmol; TCI America) was added DIPEA(0.45 mL, 2.61 mmol) and the reaction was stirred at 50° C. for 2 h. Thereaction was quenched with sat. aqueous NaHCO₃ solution and extractedwith EtOAc, the organic phase was washed with brine, dried overmagnesium sulfate and concentrated. The crude product was purified bysilica gel chromatography (0-30% EtOAc/hexanes) to yield an inseparablemixture of diastereomers 13-1 and 13-2 (338 mg). LCMS-ESI (m/z): [M+H]⁺calcd for C₃₉H₅₆ClN₄O₇: 727.38. found: 727.46.

Step 2. Preparation of diastereomer mixture 13-3 and 13-4: To a solutionof the mixture of 13-1 and 13-2 (338 mg, 0.46 mmol), TEA (0.10 mL, 0.69mmol) and potassium vinyltrifluoroborate (93 mg, 0.69 mmol) in EtOH (30mL) was added PdCl₂(dppf) (38 mg, 0.046 mmol, Strem Chemicals). Thereaction was deoxygenated with N₂ for 10 min and heated to 80° C. for 1h. The reaction was quenched with sat. aqueous NaHCO₃ solution andextracted with EtOAc, washed subsequently with brine, dried overmagnesium sulfate and concentrated. The residue was purified usingsilica gel chromatography to give an inseparable mixture ofdiastereomers 13-3 and 13-4 (285 mg). LCMS-ESI+ (m/z): [M+H]⁺ calcd forC₄₁H₅₉N₄O₇: 719.44. found: 719.70.

Step 3 and 4. Preparation of 13-5: To a solution of the diastereomericmixture 13-3 and 13-4 (285 mg, 0.40 mmol) in DCE (100 mL) was added Zhan1B catalyst (30 mg, 0.04 mmol, Strem) and the reaction was deoxygenatedfor 30 minutes with N₂. The reaction was heated to 100° C. for 45 min,allowed to cool to rt and concentrated. The crude product was purifiedby silica gel chromatography to produce macrocyclic olefin product (125mg; LCMS-ESI (m/z): [M+H]⁺ calcd for C₃₉H₅₅N₄O₇: 691.41. found: 691.58)that was taken up in EtOH (6 mL) and treated with Pd/C (10%, 120 mg).The atmosphere was replaced with hydrogen and stirred at rt for 1.5 h.The reaction was filtered over Celite, washed with EtOAc andconcentrated to give 13-5 as an oil (125 mg) that was used subsequentlywithout further purification. LCMS-ESI (m/z): [M+H]⁺ calcd forC₃₉H₅₇N₄O₇: 693.42. found: 693.46.

Step 5. Preparation of 13-6: To a solution of 13-5 (50 mg, 0.072 mmol)in DCM (4 mL) was added TFA (1 mL) and stirred at rt for 6 h. Thereaction was diluted with EtOAc, washed with H₂O, aqueous pH 7 buffer,dried over magnesium sulfate, and concentrated to give 13-6 as a residuethat was used subsequently without further purification. LCMS-ESI (m/z):[M+H]⁺ calcd for C₃₅H₄₉N₄O₇: 637.36. found: 637.40.

Step 6. Preparation of Example 13: To a solution of 13-6 (46 mg, 0.072mmol), Intermediate A9 (28 mg, 0.11 mmol), TBTU (34 mg, 0.10 mmol) andDMAP (13 mg, 0.11 mmol) in DCM (5 mL) was added DIPEA (0.038 mL, 0.22mmol) and the reaction was stirred at rt for 16 h. The reaction wasquenched with water, diluted with EtOAc, washed with sat. aqueousNaHCO₃, brine, dried over magnesium sulfate, and concentrated. The crudematerial was purified by reverse phase HPLC (Gemini, 30-85%MeCN/H₂O+0.1% TFA) and lyophilized to give Example 13 (14.5 mg) as a TFAsalt. Analytic HPLC RetTime: 9.39 min. LCMS-ESI (m/z): [M+H]⁺ calcd forC₄₃H₅₉F₂N₆O₉S: 873.40. found: 873.42. ¹H NMR (400 MHz, CD₃OD) δ 9.28 (s,1H), 7.82 (d, J=9.2 Hz, 1H), 7.26 (dd, J=6.4, 2.8 Hz, 1H), 7.19 (d,J=2.8 Hz, 1H), 6.04-5.74 (m, 2H), 5.50 (s, 1H), 4.55 (d, J=7.6 Hz, 1H),4.47 (s, 1H), 4.26-4.16 (m, 2H), 3.94 (s, 3H), 3.03-2.95 (m, 2H),2.78-2.66 (m, 2H), 2.17 (br, 2H), 2.05 (s, 3H), 1.90-1.85 (m, 1H),1.76-1.74 (m, 2H), 1.61-1.21 (m, 20H), 1.15-1.11 (m, 2H), 1.08 (s, 9H),0.93-0.90 (m, 1H).

Example 14 Preparation of(1aR,5S,8S,9S,10R,22aR)-5-cyclopentyl-N-[(1R,2R)-2-(difluoromethyl)-1-{[(1-methylcyclopropyl)sulfonyl]carbamoyl}cyclopropyl]-9-ethyl-14-methoxy-3,6-dioxo-1,1a,3,4,5,6,9,10,18,19,20,21,22,22a-tetradecahydro-8H-7,10-methanocyclopropa[18,19][1,10,3,6]dioxadiazacyclononadecino[11,12-b]quinoxaline-8-carboxamide

Step 1. Preparation of 14-1: To a solution of 1-2 (223 mg, 0.50 mmol)and Intermediate D2 (221 mg, 0.75 mmol) in acetonitrile (5 mL) was addedHATU (306 mg, 0.80 mmol) followed by DIPEA (0.43 mL, 2.5 mmol) at roomtemperature. After 19 h, solvent was removed under reduced pressure andthe resulting residue was diluted with ethyl acetate (15 mL). Theresulting solution was washed with 1 M aqueous HCl (10 mL). The aqueouslayer was extracted with ethyl acetate (2×10 mL) and combined organiclayer was washed with brine (15 mL), dried over anhydrous magnesiumsulfate and concentrated. The resulting crude residue was purified viasilica gel chromatography (0-100% ethyl acetate/hexanes gradient) toafford 14-1 (173 mg) as colorless oil. LCMS-ESI (m/z): [M+H]⁺ calcd forC₃₆H₅₀ClN₄O₇: 685.33. found: 685.49.

Step 2. Preparation of 14-2: To a solution of 14-1 (173 mg, 0.25 mmol)in EtOH (3 mL) was added potassium vinyltrifluoroborate (51 mg, 0.38mmol), PdCl₂(dppf) (21 mg, 0.025 mmol) and TEA (0.053 mL, 0.38 mmol)sequentially and the resulting mixture was heated to 80° C. After 1 h,additional potassium vinyltrifluoroborate (17 mg, 0.12 mmol) was addedand continued stirring at 80° C. After 2.5 h, additional potassiumvinyltrifluoroborate (8 mg, 0.06 mmol) was added and the reaction wasstirred for additional 10 minutes at 80° C. The reaction was cooled toroom temperature, diluted with ethyl acetate (20 mL), and washed withbrine (20 mL). Aqueous layer was extracted with ethyl acetate (10 mL),and the combined organic layer was dried over anhydrous magnesiumsulfate and concentrated to afford 14-2 as a residue which was used itwithout purification in the next step. LCMS-ESI (m/z): [M+H]⁺ calcd forC₃₈H₅₃N₄O₇: 677.38. found: 677.50.

Step 3. Preparation of 14-3: To a solution of 14-2 in deoxygenated DCE(0.006 M) was added Zhan 1B catalyst (18 mg, 0.025 mmol, Strem) and thereaction was deoxygenated for another 10 minutes with Ar. The reactionwas heated to 100° C. After 1.5 h, Zhan 1B catalyst (9 mg, 0.012 mmol)was added and the reaction was stirred for another 30 min. The reactionmixture was allowed to cool to rt and concentrated to 4-5 mL volume.This was directly purified by silica gel chromatography to afford 14-3as a brown oil (70 mg). LCMS-ESI (m/z): [M+H]⁺ calcd for C₃₆H₄₉N₄O₇:649.35. found: 649.50.

Step 4. Preparation of 14-4: To a solution of 14-3 (70 mg, 0.11 mmol) inEtOH (5 mL) was added Pd/C (10 wt % Pd, 12 mg) under argon. Theatmosphere was replaced with hydrogen and the reaction was stirred at rtfor 16 h. The reaction was filtered over Celite, washed with EtOH andconcentrated to give 14-4 as a brown oil that was used subsequentlywithout further purification. LCMS-ESI (m/z): [M+H]⁺ calcd forC₃₆H₅₁N₄O₇: 651.37. found: 651.60.

Step 5. Preparation of 14-5: To a solution of 14-4 (70 mg, 0.11 mmol) inDCM (3 mL) was added TMSOTf (0.103 mL, 0.53 mmol) and the reaction wasstirred at rt for 1 h. The reaction was concentrated to afford 14-5which was used it for the next step without purification. LCMS-ESI(m/z): [M+H]⁺ calcd for C₃₂H₄₃N₄O₇: 595.31. found: 595.43.

Step 6. Preparation of Example 14: To a solution of 14-5 (36.8 mg, 0.06mmol) and Intermediate A10 (28 mg, 0.09 mmol) in acetonitrile (1.5 mL)was added HATU (38 mg, 0.1 mmol) followed by DIPEA (0.065 mL, 0.37 mmol)at room temperature. After 20 minutes, the reaction mixture was directlypurified by reverse phase HPLC (Gemini 5u C18 110 Å column, 15-100%MeCN/H₂O+0.1% TFA) and lyophilized to afford Example 14 as a yellowsolid (24 mg) as a TFA salt. Analytic HPLC RetTime: 9.03 min. LCMS-ESI(m/z): [M+H]⁺ calcd for C₄₁H₅₅F₂N₆O₉S: 845.4. found: 845.6. ¹H NMR (400MHz, CD₃OD) δ 9.31 (s, 1H), 7.80 (d, J=9.1 Hz, 1H), 7.23 (dd, J=9.1, 2.8Hz, 1H), 7.16 (d, J=2.7 Hz, 1H), 6.03-5.66 (m, 2H), 4.53 (dd, J=13.2,9.6 Hz, 2H), 4.18 (dd, J=17.2, 7.1 Hz, 2H), 3.92 (s, 3H), 3.68 (dt,J=6.8, 2.8 Hz, 1H), 3.13 (quin, J=1.7 Hz, 1H), 3.02-2.92 (m, 1H),2.85-2.78 (m, 1H), 2.62-2.55 (m, 1H), 2.30-2.17 (m, 1H), 2.02 (s, 2H),1.97-1.86 (m, 3H), 1.86-1.79 (m, 1H), 1.80-1.41 (m, 17H), 1.40-1.28 (m,3H), 1.22 (t, J=7.4 Hz, 3H), 1.03-0.87 (m, 4H), 0.76-0.68 (m, 1H),0.51-0.44 (m, 1H).

Example 15 Preparation of(1aR,5S,8S,9S,10R,22aR)-5-cyclopentyl-N-[(1R,2R)-1-[(cyclopropylsulfonyl)carbamoyl]-2-(difluoromethyl)cyclopropyl]-9-ethyl-14-methoxy-3,6-dioxo-1,1a,3,4,5,6,9,10,18,19,20,21,22,22a-tetradecahydro-8H-7,10-methanocyclopropa[18,19][1,10,3,6]dioxadiazacyclononadecino[11,12-b]quinoxaline-8-carboxamide

Step 1. Preparation of Example 15. To a solution of 14-5 (27 mg, 0.045mmol) and Intermediate A9 (20 mg, 0.067 mmol) in acetonitrile (1.3 mL)was added HATU (27 mg, 0.072 mmol) followed by DIPEA (0.047 mL, 0.27mmol) at room temperature. After 20 minutes, the reaction mixture wasdirectly purified by reverse phase HPLC (Gemini 5u C18 110 Å column,15-100% MeCN/H₂O+0.1% TFA) and lyophilized to afford Example 15 as ayellow solid (18.6 mg) as a TFA salt. Analytic HPLC RetTime: 8.89 min.LCMS-ESI (m/z): [M+H]⁺ calcd for C₄₀H₅₃F₂N₆O₉S: 831.4. found: 831.6. ¹HNMR (400 MHz, CD₃OD) (9.32 (s, 1H), 7.79 (d, J=9.1 Hz, 1H), 7.23 (dd,J=9.1, 2.8 Hz, 1H), 7.16 (d, J=2.8 Hz, 1H), 6.03-5.66 (m, 2H), 4.53 (t,J=10.0 Hz, 2H), 4.22-4.14 (m, 2H), 3.92 (s, 3H), 3.67 (dt, J=6.5, 2.9Hz, 1H), 3.13 (quin, 1.6 Hz, 1H), 3.04-2.92 (m, 3H), 2.85-2.77 (m, 1H),2.63-2.55 (m, 1H), 2.26-2.19 (m, 1H), 2.05-2.02 (m, 2H), 1.99-1.86 (m,3H), 1.84-1.42 (m, 12H), 1.41-1.25 (m, 4H), 1.22 (t, J=7.2 Hz, 3H),1.15-1.03 (m, 3H), 1.01-0.90 (m, 2H), 0.76-0.68 (m, 1H), 0.49-0.45 (m,1H).

Example 16 Preparation of(1aR,5S,8S,9S,10R,22aR)-5-cyclohexyl-N-[(1R,2R)-2-(difluoromethyl)-1-{[(1-methylcyclopropyl)sulfonyl]carbamoyl}cyclopropyl]-9-ethyl-14-methoxy-3,6-dioxo-1,1a,3,4,5,6,9,10,18,19,20,21,22,22a-tetradecahydro-8H-7,10-methanocyclopropa[18,19][1,10,3,6]dioxadiazacyclononadecino[11,12-b]quinoxaline-8-carboxamide

Step 1. Preparation of 16-1: To a solution of Intermediate D3 (190 mg,0.60 mmol) and 1-2 (264 mg, 0.60 mmol) in DMF (5 mL) was added DIPEA(0.31 mL, 1.8 mmol) followed by COMU (257 mg, 0.60 mmol) at rt. After 2h, the solvent was removed under reduced pressure and the resultingresidue diluted with ethyl acetate (15 mL). The resulting solution waswashed with 10% aqueous citric acid solution. The aqueous layer wasextracted with ethyl acetate (2×10 mL) and combined organic layer waswashed with brine (15 mL), dried over anhydrous magnesium sulfate andconcentrated. The resulting crude residue was purified via silica gelchromatography to afford 16-1 (260 mg) as a colorless oil. LCMS-ESI(m/z): [M+H]⁺ calcd for C₃₇H₅₁ClN₄O₇: 700.28. found: 700.03.

Step 2. Preparation of 16-2: To a solution of 16-1 (260 mg, 0.37 mmol)in EtOH (5 mL) were added potassium vinyltrifluoroborate (75 mg, 0.56mmol), PdCl₂(dppf) (30 mg, 0.037 mmol) and TEA (0.079 mL, 0.56 mmol)sequentially. The reaction was deoxygenated with Ar for 12 min and washeated to 78° C. for 2 h. The reaction was cooled to rt, diluted withethyl acetate (20 mL), and washed with brine (20 mL). The aqueous layerwas extracted with ethyl acetate (10 mL), and the combined organiclayers were dried over anhydrous magnesium sulfate and concentrated toafford crude residue. The resulting crude residue was purified viasilica gel chromatography to afford 16-2 as a yellow oil (250 mg).LCMS-ESI (m/z): [M+H]⁺ calcd for C₃₉H₅₄N₄O₇: 691.87. found: 691.54.

Step 3. Preparation of 16-3: To a solution of 16-2 (250 mg, 0.36 mmol)in deoxygenated DCE (0.005 M) was added Zhan 1B catalyst (26 mg, 0.036mmol, Strem) and the reaction was deoxygenated for another 10 minuteswith Ar. The reaction was heated to 70° C. for 2 h. The reaction mixturewas allowed to cool to rt and concentrated. The resulting residue wasdirectly purified by silica gel chromatography to afford 16-3 as ayellow oil (250 mg). LCMS-ESI⁺ (m/z): [M+H]⁺ calcd for C₃₇H₅₀N₄O₇:663.82. found: 663.42.

Step 4. Preparation of 16-4: To a solution of 16-3 (200 mg, 0.3 mmol) inEtOAc (10 mL) was added Pd/C (10 wt % Pd, 100 mg) under argon. Theatmosphere was replaced with hydrogen and the reaction was stirred at rtfor 1.5 h. The reaction was filtered over Celite, washed with EtOH andconcentrated to give 16-4 as an oil (180 mg) that was used subsequentlywithout further purification. LCMS-ESI⁺ (m/z): [M+H]⁺ calcd forC₃₇H₅₂N₄O₇: 665.83. found: 665.36.

Step 5. Preparation of 16-5: To a solution of 16-4 (165 mg, 0.25 mmol)in DCM (5 mL) was added TFA (2 mL) and the reaction was stirred at rtfor 4 h. The solvent was removed under reduced pressure the reaction wasdiluted with ethyl acetate (15 mL). The resulting solution was washedwith sat. aqueous NaHCO₃ and concentrated to afford 16-5 which was usedin the next step without further purification. LCMS-ESI (m/z): [M+H]⁺calcd for C₃₃H₄₄N₄O₇: 609.73. found: 609.47.

Step 6. Preparation of Example 16: To a solution of 16-5 (70 mg, 0.12mmol) and Intermediate A10 (65 mg, 0.21 mmol) in DCM (1 mL) was addedDIPEA (0.08 mL, 0.46 mmol) followed by HATU (88 mg, 0.23 mmol). Thereaction was stirred at room temperature for 3 h. The reaction wasdiluted with EtOAc and washed with aqueous NH₄Cl and brine. The crudematerial was purified by reverse phase HPLC (Gemini column, 58-98%MeCN/H₂O+0.1% TFA) and lyophilized to afford Example 16 (40 mg) as a TFAsalt. Analytic HPLC RetTime: 9.21 min. LCMS-ESI (m/z): [M+H]⁺ calcd forC₄₂H₅₆F₂N₆O₉S: 859.99. found: 859.60. ¹H NMR (400 MHz, CD₃OD) δ 9.28 (s,1H), 7.76 (d, J=9.2 Hz, 1H), 7.18 (d, J=9.2 Hz, 1H), 7.10 (s, 1H),5.97-5.82 (m, 2H), 4.88 (m, 2H), 4.51-4.46 (m, 3H), 4.19-4.11 (m, 3H),3.90 (s, 3H), 3.70-3.29 (m, 6H), 2.97-2.52 (m, 3H), 2.06-1.41 (m, 20H),1.39-1.17 (m, 4H), 1.09-0.89 (m, 4H), 0.65 (m, 1H), 0.46-0.44 (m, 1H).

Example 17 Preparation of(1aR,5S,8S,9S,10R,22aR)-5-tert-butyl-N-[(1R,2R)-2-(difluoromethyl)-1-{[(1-methylcyclopropyl)sulfonyl]carbamoyl}cyclopropyl]-9-ethyl-18,18-difluoro-14-methoxy-3,6-dioxo-1,1a,3,4,5,6,9,10,18,19,20,21,22,22a-tetradecahydro-8H-7,10-methanocyclopropa[18,19][1,10,3,6]dioxadiazacyclononadecino[11,12-b]quinoxaline-8-carboxamide

Steps 1 and 2. Preparation of 17-2: A mixture of Intermediate B4 (273mg, 0.865 mmol), Intermediate E3 (234 mg, 0.865 mmol), and cesiumcarbonate (310 mg, 0.952 mmol) in MeCN (2.5 mL) was heated at 85° C. for36 hours. In an alternative process, DMF was used as the solvent. Water(10 mL) was added and the mixture was extracted with ethyl acetate. Theorganic phase was dried over sodium sulfate, filtered and concentratedto afford 17-1, which was used subsequently without further purificationor after chromatography purification. The residue was treated with 35equiv 4 N HCl in dioxane at rt for 2.5 hours. Upon addition of diethylether, the hydrochloride salt of 17-2 precipitated. The salt wascollected by vacuum filtration and dried under reduced pressure (375mg). In an alternative process, the deprotection was conducted in thepresence of MSA in tBuOAc and DCM. LCMS-ESI (m/z): [M+H]⁺ calcd forC₂₃H₃₀F₂N₃O₄: 450.2. found: 450.1.

Step 3. Preparation of 17-3: A mixture of 17-2 (370 mg, 0.761 mmol),Intermediate D11 (205 mg, 0.761 mmol), HATU (347 mg, 0.914 mmol) andDIPEA (0.795 mL, 4.57 mmol) in DMF (3 mL) was stirred at rt overnight.The mixture was diluted with 100 mL water and extracted withdichloromethane. The organic phase was dried over sodium sulfate,filtered and concentrated. The crude product mixture was purified bysilica gel chromatography (EtOAc in hexanes: 30%) to give 17-3 (236 mg).In an alternative process, 17-2 and Intermediate D11 were mixed with EDCand HOBT in the presence of NMM in DMF to give 17-3. LCMS-ESI (m/z):[M+H]⁺ calcd for C₃₇H₅₁F₂N₄O₇: 701.4. found: 701.3.

Step 4. Preparation of 17-4: A solution of 17-3 (236 mg, 0.34 mmol) inDCE (67 mL) was deoxygenated with argon for 40 minutes. Zhan 1B catalyst(25 mg, 0.034 mmol, Strem) was added and the reaction was heated in a100° C. oil bath for 40 minutes. Solvent was removed under reducedpressure and the residue was purified by silica gel chromatography(EtOAc in hexanes: 5% to 65%) to give the 17-4 (229 mg). LCMS-ESI (m/z):[M-F]⁺ calcd for C₃₅H₄₆FN₄O₇: 653.3. found: 653.2.

Step 5. Preparation of 17-5: A solution of 17-4 (229 mg, 0.34 mmol) in50 mL ethanol was hydrogenated at 1 atm hydrogen gas over 220 mg of 10%wt Pd/C (wet) for 2.5 hours. Filtration through Celite and concentrationunder reduced pressure gave a crude residue of 17-5 (184 mg). In analternative process, 17-4 was hydrogenated at hydrogen gas in thepresence of Rh. LCMS-ESI⁺ (m/z): [M+H]⁺ calcd for C₃₅H₄₉F₂N₄O₇: 675.4.found: 675.3.

Step 6. Preparation of 17-6: Ester 17-5 (184 mg, 0.27 mmol) in 2 mL DCMwas treated with 1 mL TFA and stirred at rt for 3 h. The reactionmixture was concentrated and then partitioned between water and ethylacetate. The organic phase was washed with water, dried over anhydroussodium sulfate, filtered and concentrated to give 17-6 (153 mg).LCMS-ESI⁺ (m/z): [M+H]⁺ calcd for C₃₁H₄₁F₂N₄O₇: 619.3. found: 619.2.

Step 7. Preparation of Example 17: A mixture of carboxylic acid 17-6(153 mg, 0.247 mmol), Intermediate A10 (90 mg, 0.297 mmol), HATU (113mg, 0.297 mmol), DMAP (45 mg, 0.37 mmol) and DIPEA (0.215 mL, 1.24 mmol)in DMF (1.5 mL) was stirred at rt for 40 minutes. The mixture wasdiluted with 2 N aqueous HCl (2 mL) and extracted with dichloromethane.The organic phase was dried over sodium sulfate, filtered andconcentrated. The crude product mixture was purified by silica gelchromatography (EtOAc in hexanes: 30%-95%) to give Example 17 (95 mg).Analytic HPLC RetTime: 8.79 min. LCMS-ESI⁺ (m/z): [M+H]⁺ calcd forC₄₀H₅₃F₄N₆O₉S: 869.3. found: 869.2. ¹H NMR (400 MHz, CDCl₃) δ 9.948 (brs, 1H), 7.99 (d, J=9.2 Hz, 1H), 7.29 (dd, J=8.8, 2.4 Hz, 1H), 7.09 (d,J=2.8 Hz, 1H), 6.57 (br s, 1H), 5.97 (td, J_(H-F)=52 Hz, J=6.8 Hz, 1H),5.92 (d, J=3.6 Hz, 1H), 5.322 (d, J=9.6 Hz, 1H), 4.42 (ap d, J=7.2 Hz,1H), 4.40 (ap s, 1H), 4.34 (ap d, J=10 Hz, 1H), 4.08 (dd, J=12.0, 3.6Hz, 1H), 3.99-3.94 (m, 1H), 3.96 (s, 3H), 3.67 (m, 1H), 2.52 (m, 2H),2.06 (m, 1H), 1.93 (m, 2H), 1.77 (m, 2H), 1.63 (m, 3H), 1.50 (s, 3H),1.56-1.42 (m, 4H), 1.25 (m, 1H), 1.19 (t, J=7.2 Hz, 3H), 1.09 (s, 9H),1.10-0.93 (m, 2H), 0.85 (m, 2H), 0.69 (m, 1H), 0.49 (m, 1H).

Example 18 Preparation of(1aR,5S,8S,9S,10R,22aR)-5-tert-butyl-N-[(1R,2R)-2-(difluoromethyl)-1-{[(1-methylcyclopropyl)sulfonyl]carbamoyl}cyclopropyl]-14-methoxy-9-methyl-3,6-dioxo-1,1a,3,4,5,6,9,10,18,19,20,21,22,22a-tetradecahydro-8H-7,10-methanocyclopropa[18,19][1,10,3,6]dioxadiazacyclononadecino[11,12-b]quinoxaline-8-carboxamide

Step 1. Preparation of 18-1: Intermediate B1 (1.94 g, 6.44 mmol) wasdissolved in MeCN (30 mL) under Ar. Intermediate E1 (2.02 g, 7.4 mmol)and Cs₂CO₃ (7.5 mmol) were added, and the resulting mixture was stirredfor 8 h at rt. Additional Intermediate E1 (200 mg, 0.73 mmol) and Cs₂CO₃(245 mg, 0.75 mmol) were added and the reaction mixture was stirred anadditional 15 h. The reaction mixture was filtered through Celite withEtOAc and concentrated. The resulting crude residue was dissolved inCH₂Cl₂, concentrated onto 12 g silica gel, and purified by silica gelchromatography (5% to 20% EtOAc in hexanes) to provide 18-1 as a whitefoam (2.63 g). LCMS-ESI (m/z): [M+H]⁺ calcd for C₂₄H₃₃ClN₃O₆: 494.2.found: 494.1.

Step 2. Preparation of 18-2: Substituted quinoxaline 18-1 (905 mg, 1.84mmol) was dissolved in tert-butyl acetate (7 mL) and CH₂Cl₂ (1.75 mL).MeSO₃H (600 μL, 9.2 mmol) was added dropwise over 45 s, and theresulting yellow solution was stirred at rt for 50 min. AdditionalMeSO₃H (100 μL, 1.5 mmol) was added in dropwise fashion and the reactionwas stirred an additional 10 min. The reaction mixture was transferredto a stirred mixture of EtOAc (20 mL) and saturated aqueous NaHCO₃ (30mL). The phases were separated, and the aqueous phase was extracted withEtOAc (20 mL). The combined organic phase was dried over Na₂SO₄,filtered, and concentrated to afford amine 18-2 as a colorless residue(680 mg). LCMS-ESI (m/z): [M+H]⁺ calcd for C₁₉H₂₅ClN₃O₄: 394.2. found:394.2.

Step 3. Preparation of 18-3: Amine 18-2 (680 mg, 1.73 mmol) andIntermediate D1 (600 mg, 2.1 mmol) were dissolved in DMF (10 mL). DIPEA(925 μL, 5.30 mmol) was added followed by HATU (880 mg, 2.3 mmol). Thereaction was stirred 110 min at rt and was diluted with saturatedaqueous NaHCO₃ (30 mL) and EtOAc (30 mL). The phases were separated andthe organic phase was washed with half-saturated brine (2×40 mL), driedover anhydrous Na₂SO₄, filtered and concentrated to a crude residue.Purification by silica gel chromatography (10% to 20% EtOAc in hexanes)provided 18-3 as a colorless residue (703 mg). LCMS-ESI⁺ (m/z): [M+H]⁺calcd for C₃₄H₄₈ClN₄O₇: 659.3. found: 659.4.

Step 4. Preparation of 18-4: A stirred heterogeneous mixture of 18-3(703 mg, 1.07 mmol), PdCl₂(dppf)*CH₂Cl₂ (48 mg, 0.059 mmol) andpotassium vinyltrifluoroborate (290 mg, 2.16 mmol) in EtOH (11 mL) wassparged with argon for 15 min. Triethylamine (320 μL, 2.3 mmol) wasadded and the mixture was heated to 75° C. for 70 min. The reactionmixture was cooled to ambient temperature and was diluted with EtOAc (40mL) and half-saturated brine (30 mL). The phases were separated and theorganic phase was dried over Na₂SO₄, filtered, and concentrated.Purification by silica gel chromatography (10% to 20% to 30% EtOAc inhexanes) provided 18-4 as a yellow residue (490 mg). LCMS-ESI⁺ (m/z):[M+H]⁺ calcd for C₃₆H₅₁N₄O₇: 651.4. found: 651.3.

Step 5. Preparation of 18-5: 18-4 (490 mg, 0.179 mmol) was dissolved inDCE (250 mL) and the solution was sparged with Ar for 15 min. Zhan 1Bcatalyst (66 mg, 0.090 mmol, Strem) was added as a solution in DCE (5mL) and the resulting solution was stirred at 85° C. under Ar for 105min. The reaction mixture was cooled to rt and was adsorbed onto silicagel (7.5 g). Purification by silica gel chromatography (10% to 30% EtOAcin hexanes) provided 18-5 as an amorphous residue (290 mg). LCMS-ESI⁺(m/z): [M+H]⁺ calcd for C₃₄H₄₇N₄O₇: 623.3. found: 623.3.

Step 6: Preparation of 18-6: Olefin 18-5 (290 mg, 0.072 mmol) wasdissolved in EtOAc (5.5 mL) and EtOH (5.5 mL) and the reaction vesselwas purged with Ar. Pd/C (10 wt % Pd, 92 mg) was added in a singleportion and the reaction vessel was purged twice with H₂. The reactionwas stirred at rt under 1 atm H₂ for 1.5 h and was filtered through apad of Celite and concentrated to afford a crude residue of 18-6 thatwas used without further purification (LCMS-ESI⁺ (m/z): [M+H]⁺ calcd forC₃₄H₄₉N₄O₇: 625.4. found: 625.0.

Step 7. Preparation of 18-7: 18-6 (0.466 mmol) was dissolved in CH₂Cl₂(4.3 mL) under Ar. TMSOTf (210 μL, 1.16 mmol) was added dropwise over 30s. The reaction was stirred 65 min and an additional portion of TMSOTf(50 μL, 0.28 mmol) was added. The reaction was stirred an additional 100min and an additional portion of TMSOTf (100 μL, 0.55 mmol) was added.The reaction was stirred an additional 105 min and was concentrated invacuo. The resulting crude residue was dissolved in CH₂Cl₂ (20 mL) and0.2 M aqueous NaOH (10 mL) was added. The mixture was stirred for 5 minand was acidified with 1 M aqueous HCl (20 mL). The phases wereseparated, and the aqueous phase was extracted with CH₂Cl₂ (2×20 mL).The combined organic phase was dried over MgSO₄, filtered, andconcentrated to afford 18-7 as a brown solid (273 mg). LCMS-ESI (m/z):[M+H]⁺ calcd for C₃₀H₄₁N₄O₇: 569.3. found: 568.9.

Step 8. Preparation of Example 18: To a suspension of acid 18-7 (28 mg,0.049 mmol) and Intermediate A10 (26.5 mg, 0.087 mmol) in MeCN (1.3 mL)was added DIPEA (55 μL, 0.31 mmol). To the resulting solution was addedHATU (30.5 mg, 0.080 mmol). The reaction was stirred at rt for 1 h andan additional portion of Intermediate A10 (3 mg, 0.01 mmol) was added.After an additional 15 min, the reaction was diluted with EtOAc (30 mL)and 1 M aqueous HCl (20 mL). The phases were separated and the aqueousphase was extracted with EtOAc (30 mL). The combined organic phase wasdried over Na₂SO₄, filtered, and concentrated to afford a crude residue.Purification by silica gel chromatography (10% to 40% acetone inhexanes) provided an amorphous residue that was lyophilized from waterand MeCN to provide Example 18 as a white amorphous solid (26.4 mg).Analytic HPLC RetTime: 8.42 min. LCMS-ESI⁺ (m/z): [M+H]⁺ calcd forC₃₉H₅₃F₂N₆O₉S: 819.4. found: 819.1. ¹H NMR (300 MHz, CDCl₃) δ 9.68 (s,1H), 7.82 (d, J=9.1 Hz, 1H), 7.19 (dd, J=9.1, 2.8 Hz, 1H), 7.08 (d,J=2.6 Hz, 1H), 6.86 (s, 1H), 6.14-5.70 (m, 1H), 5.65 (d, J=9.9 Hz, 1H),5.56-5.50 (m, 1H), 4.53-4.40 (m, 3H), 4.12 (dd, J=11.9, 4.3 Hz, 1H),3.93 (s, 3H), 3.81-3.74 (m, 1H), 3.06-2.64 (m, 4H), 2.10-1.35 (m, 13H),1.13 (d, J=7.5 Hz, 3H), 1.09 (s, 9H), 1.04-0.65 (m, 6H), 0.52-0.41 (m,1H).

Example 19 Preparation of(1aR,5S,8S,9S,10R,22aR)-5-tert-butyl-N-[(1R,2R)-1-[(cyclopropylsulfonyl)carbamoyl]-2-(difluoromethyl)cyclopropyl]-14-methoxy-9-methyl-3,6-dioxo-1,1a,3,4,5,6,9,10,18,19,20,21,22,22a-tetradecahydro-8H-7,10-methanocyclopropa[18,19][1,10,3,6]dioxadiazacyclononadecino[11,12-b]quinoxaline-8-carboxamide

Step 1. Preparation of Example 19: To a suspension of acid 18-7 (8.8 mg,0.015 mmol) and Intermediate A9 (7.4 mg, 0.025 mmol) in MeCN (0.5 mL)was added DIPEA (14 μL, 0.08 mmol). To the resulting solution was addedHATU (9.1 mg, 0.024 mmol). The reaction was stirred at rt for 1 h and anadditional portion of Intermediate A9 (5 mg, 0.02 mmol) and HATU (5 mg,0.01 mmol) were added. After an additional 1.5 h, the reaction wasdiluted with EtOAc (30 mL), 0.2 M aqueous HCl (10 mL), and brine (10mL). The phases were separated and the aqueous phase was extracted withEtOAc (30 mL). The combined organic phase was dried over Na₂SO₄,filtered, and concentrated to afford a crude residue. Purification bysilica gel chromatography (10% to 40% acetone in hexanes) provided aresidue that was lyophilized from water and MeCN to provide Example 19as a white amorphous solid (8.5 mg). Analytic HPLC RetTime: 8.69 min.LCMS-ESI⁺ (m/z): [M+H]⁺ calcd for C₃₈H₅₁F₂N₆O₉S: 805.3. found: 805.2. ¹HNMR (300 MHz, CDCl₃) δ 10.12 (s, 1H), 7.83 (d, J=9.1 Hz, 1H), 7.19 (dd,J=9.1, 2.7 Hz, 1H), 7.09 (d, J=2.7 Hz, 1H), 6.77 (s, 1H), 6.25-5.76 (m,1H), 5.57 (d, J=3.7 Hz, 1H), 5.51 (d, J=9.9 Hz, 1H), 4.49-4.37 (m, 3H),4.13 (dd, J=12.2, 4.3 Hz, 1H), 3.94 (s, 3H), 3.79-3.72 (m, 1H),3.01-2.69 (m, 4H), 2.13-2.06 (m, 1H), 2.01-1.22 (m, 9H), 1.14 (d, J=7.2Hz, 3H), 1.09 (s, 9H), 1.06-0.82 (m, 6H), 0.76-0.62 (m, 1H), 0.54-0.41(m, 1H).

Example 20 Preparation of(1aR,5S,8S,9S,10R,22aR)-5-tert-butyl-N-{(1R,2R)-1-[(cyclopropylsulfonyl)carbamoyl]-2-ethylcyclopropyl}-14-methoxy-9-methyl-3,6-dioxo-1,1a,3,4,5,6,9,10,18,19,20,21,22,22a-tetradecahydro-8H-7,10-methanocyclopropa[18,19][1,10,3,6]dioxadiazacyclononadecino[11,12-b]quinoxaline-8-carboxamide

Step 1. Preparation of Example 20: To a suspension of acid 18-7 (10 mg,0.018 mmol) and Intermediate A3 (6.3 mg, 0.023 mmol) in MeCN (0.5 mL)was added DIPEA (15 μL, 0.086 mmol). To the resulting solution was addedHATU (9.0 mg, 0.024 mmol). The reaction was stirred at rt for 2.5 h andan additional portion of Intermediate A3 (6.5 mg, 0.024 mmol) was added.After an additional 45 min, the reaction was diluted with EtOAc (2 mL)and 1 M aqueous HCl (1.5 mL). The phases were separated and the aqueousphase was extracted with EtOAc (4×1.5 mL). The combined organic phasewas dried over Na₂SO₄, filtered, and concentrated to afford a cruderesidue. Purification by silica gel chromatography (20% to 25% to 30%acetone in hexanes) provided a residue that was lyophilized from waterand MeCN to provide Example 20 as a white amorphous solid (8.0 mg).Analytic HPLC RetTime: 8.40 min. LCMS-ESI⁺ (m/z): [M+H]⁺ calcd forC₃₉H₅₅N₆O₉S: 783.4. found: 783.2. ¹H NMR (300 MHz, CDCl₃) δ 9.98 (s,1H), 7.83 (d, J=9.1 Hz, 1H), 7.19 (dd, J=9.1, 2.8 Hz, 1H), 7.09 (d,J=2.7 Hz, 1H), 6.42 (s, 1H), 5.57 (d, J=3.8 Hz, 1H), 5.36 (d, J=9.9 Hz,1H), 4.48-4.34 (m, 3H), 4.11 (dd, J=11.8, 4.1 Hz, 1H), 3.94 (s, 3H),3.79-3.72 (m, 1H), 2.98-2.68 (m, 4H), 1.95-0.80 (m, 33H), 0.76-0.61 (m,1H), 0.53-0.41 (m, 1H).

Example 21 Preparation of(1aR,5S,8S,9S,10R,22aR)-5-tert-butyl-N-[(1R,2R)-2-ethyl-1-{[(1-methylcyclopropyl)sulfonyl]carbamoyl}cyclopropyl]-14-methoxy-9-methyl-3,6-dioxo-1,1a,3,4,5,6,9,10,18,19,20,21,22,22a-tetradecahydro-8H-7,10-methanocyclopropa[18,19][1,10,3,6]dioxadiazacyclononadecino[11,12-b]quinoxaline-8-carboxamide

Step 1. Preparation of Example 21: To a suspension of acid 18-7 (94.9mg, 0.167 mmol) and Intermediate A4 (74.5 mg, 0.263 mmol) in MeCN (2.5mL) was added DIPEA (180 μL, 1.0 mmol). To the resulting solution wasadded HATU (9.0 mg, 0.024 mmol). The reaction was stirred at rt for 110min and additional portions of Intermediate A4 (31 mg, 0.11 mmol) andDIPEA (50 μL, 0.29 mmol) were added. After an additional 40 min, thereaction was diluted with EtOAc (30 mL), 0.2 M aqueous HCl (20 mL), andbrine (10 mL). The phases were separated and the aqueous phase wasextracted with EtOAc (20 mL). The combined organic phase was dried overNa₂SO₄, filtered, and concentrated to afford a crude residue.Purification by silica gel chromatography (10% to 40% acetone inhexanes) provided a residue that was lyophilized from water and MeCN toprovide Example 21 as a white amorphous solid (102.1 mg). Analytic HPLCRetTime: 8.83 min. LCMS-ESI⁺ (m/z): [M+H]⁺ calcd for C₄₀H₅₇N₆O₉S: 797.4.found: 797.5. ¹H NMR (400 MHz, CDCl₃) δ 9.76 (s, 1H), 7.80 (d, J=9.1 Hz,1H), 7.17 (dd, J=9.1, 2.8 Hz, 1H), 7.07 (d, J=2.7 Hz, 1H), 6.92 (s, 1H),5.58-5.42 (m, 2H), 4.48-4.36 (m, 3H), 4.09 (dd, J=11.8, 4.2 Hz, 1H),3.92 (s, 3H), 3.79-3.74 (m, 1H), 2.97-2.66 (m, 4H), 1.80-0.88 (m, 33H),0.84-0.77 (m, 1H), 0.77-0.61 (m, 2H), 0.52-0.40 (m, 1H).

Example 22 Preparation of(1aR,5S,8S,9S,10R,22aR)-5-tert-butyl-N-[(1R,2S)-1-[(cyclopropylsulfonyl)carbamoyl]-2-(2-fluoroethyl)cyclopropyl]-14-methoxy-9-methyl-3,6-dioxo-1,1a,3,4,5,6,9,10,18,19,20,21,22,22a-tetradecahydro-8H-7,10-methanocyclopropa[18,19][1,10,3,6]dioxadiazacyclononadecino[11,12-b]quinoxaline-8-carboxamide

Step 1. Preparation of Example 22: To a suspension of acid 18-7 (30.1mg, 0.0529 mmol) and Intermediate A5 (35 mg, 0.12 mmol) in MeCN (0.5 mL)was added DIPEA (85 μL, 0.49 mmol). To the resulting solution was addedHATU (34.5 mg, 0.0907 mmol). The reaction was stirred at rt for 90 minand was diluted with EtOAc (30 mL), 0.2 M aqueous HCl (20 mL), and brine(10 mL). The phases were separated and the aqueous phase was extractedwith EtOAc (30 mL). The combined organic phase was dried over Na₂SO₄,filtered, and concentrated to afford a crude residue that was dissolvedin CH₂Cl₂ and adsorbed onto 2 g silica gel. Purification by silica gelchromatography (15% to 55% acetone in hexanes) provided a residue thatwas lyophilized from water and MeCN to provide Example 22 as a whiteamorphous solid (35.5 mg). Analytic HPLC RetTime: 8.54 min. LCMS-ESI⁺(m/z): [M+H]⁺ calcd for C₃₉H₅₄FN₆O₉S: 801.4. found: 801.3. ¹H NMR (400MHz, CDCl₃) δ 9.95 (s, 1H), 7.82 (d, J=9.1 Hz, 1H), 7.19 (dd, J=9.1, 2.8Hz, 1H), 7.08 (d, J=2.7 Hz, 1H), 6.68 (s, 1H), 5.56 (d, J=3.9 Hz, 1H),5.43 (d, J=9.9 Hz, 1H), 4.57-4.29 (m, 5H), 4.12 (dd, J=11.8, 4.1 Hz,1H), 3.93 (s, 3H), 3.78-3.71 (m, 1H), 2.97-2.67 (m, 4H), 2.12-1.25 (m,14H), 1.15 (d, J=7.4 Hz, 3H), 1.10 (s, 9H), 1.06-0.89 (m, 4H), 0.76-0.62(m, 1H), 0.53-0.42 (m, 1H).

Example 23 Preparation of(1aR,5S,8S,9S,10R,22aR)-5-tert-butyl-N-[(1R,2S)-2-(2-fluoroethyl)-1-{[(1-methylcyclopropyl)sulfonyl]carbamoyl}cyclopropyl]-14-methoxy-9-methyl-3,6-dioxo-1,1a,3,4,5,6,9,10,18,19,20,21,22,22a-tetradecahydro-8H-7,10-methanocyclopropa[18,19][1,10,3,6]dioxadiazacyclononadecino[11,12-b]quinoxaline-8-carboxamide

Step 1. Preparation of Example 23: To a suspension of acid 18-7 (30.5mg, 0.0536 mmol) and Intermediate A6 (24.8 mg, 0.0824 mmol) in MeCN (0.5mL) was added DIPEA (60 μL, 0.34 mmol). To the resulting solution wasadded HATU (32.3 mg, 0.0850 mmol). The reaction was stirred at rt for 75min and an additional portion of Intermediate A6 (9 mg, 0.03 mmol) wasadded. After an additional 75 min the reaction was diluted with EtOAc(30 mL), 0.2 M aqueous HCl (20 mL), and brine (10 mL). The phases wereseparated and the aqueous phase was extracted with EtOAc (30 mL). Thecombined organic phase was dried over Na₂SO₄, filtered, and concentratedto afford a crude residue that was dissolved in CH₂Cl₂ and adsorbed onto2 g silica gel. Purification by silica gel chromatography (15% to 55%acetone in hexanes) provided a residue that was lyophilized from waterand MeCN to provide Example 23 as a white amorphous solid (37.1 mg).Analytic HPLC RetTime: 8.64 min. LCMS-ESI (m/z): [M+H]⁺ calcd forC₄₀H₅₆FN₆O₉S: 815.4. found: 815.6. ¹H NMR (400 MHz, CDCl₃) δ 9.63 (s,1H), 7.83 (d, J=9.1 Hz, 1H), 7.20 (dd, J=9.1, 2.8 Hz, 1H), 7.10 (d,J=2.7 Hz, 1H), 6.75 (s, 1H), 5.56 (d, J=3.9 Hz, 1H), 5.50 (d, J=10.0 Hz,1H), 4.56-4.34 (m, 5H), 4.13 (dd, J=11.8, 4.2 Hz, 1H), 3.95 (s, 3H),3.82-3.75 (m, 1H), 2.98-2.70 (m, 4H), 2.07-2.00 (m, 1H), 2.00-1.93 (m,1H), 1.88-1.44 (m, 12H), 1.32-1.26 (m, 1H), 1.17 (d, J=7.4 Hz, 3H), 1.12(d, J=10.6 Hz, 9H), 1.07-0.83 (m, 4H), 0.81-0.65 (m, 2H), 0.52-0.44 (m,1H).

Example 24 Preparation of(1aR,5S,8S,9S,10R,22aR)-5-tert-butyl-N-[(1R,2S)-1-[(cyclopropylsulfonyl)carbamoyl]-2-(2,2-difluoroethyl)cyclopropyl]-14-methoxy-9-methyl-3,6-dioxo-1,1a,3,4,5,6,9,10,18,19,20,21,22,22a-tetradecahydro-8H-7,10-methanocyclopropa[18,19][1,10,3,6]dioxadiazacyclononadecino[11,12-b]quinoxaline-8-carboxamide

Step 1. Preparation of Example 24: To a suspension of acid 18-7 (30.2mg, 0.0531 mmol) and Intermediate A7 (25.9 mg, 0.0850 mmol) in MeCN (0.5mL) was added DIPEA (60 μL, 0.34 mmol). To the resulting solution wasadded HATU (32 mg, 0.084 mmol). The reaction was stirred at rt for 75min and an additional portion of Intermediate A7 (3.0 mg, 0.0098 mmol)was added. After an additional 30 min the reaction was diluted withEtOAc (30 mL), 0.2 M aqueous HCl (20 mL), and brine (10 mL). The phaseswere separated and the aqueous phase was extracted with EtOAc (30 mL).The combined organic phase was dried over Na₂SO₄, filtered, andconcentrated to afford a crude residue that was dissolved in CH₂Cl₂ andadsorbed onto 2 g silica gel. Purification by silica gel chromatography(15% to 55% acetone in hexanes) provided a residue that was lyophilizedfrom water and MeCN to provide Example 24 as a white amorphous solid(35.5 mg). Analytic HPLC RetTime: 8.62 min. LCMS-ESI⁺ (m/z): [M+H]⁺calcd for C₃₉H₅₃F₂N₆O₉S: 819.4. found: 819.2. ¹H NMR (400 MHz, CDCl₃) δ9.99 (s, 1H), 7.82 (d, J=9.1 Hz, 1H), 7.19 (dd, J=9.1, 2.8 Hz, 1H), 7.08(d, J=2.7 Hz, 1H), 6.69 (s, 1H), 5.99-5.64 (m, 1H), 5.56 (d, J=3.9 Hz,1H), 5.40 (d, J=10.0 Hz, 1H), 4.47-4.39 (m, 3H), 4.14-4.08 (m, 1H), 3.93(s, 3H), 3.78-3.72 (m, 1H), 2.96-2.67 (m, 4H), 2.29-2.16 (m, 2H),1.83-1.24 (m, 12H), 1.15 (d, J=7.4 Hz, 3H), 1.09 (s, 9H), 1.05-0.82 (m,4H), 0.74-0.63 (m, 1H), 0.53-0.42 (m, 1H).

Example 25 Preparation of(1aR,5S,8S,9S,10R,22aR)-5-tert-butyl-N-[(1R,2S)-2-(2,2-difluoroethyl)-1-{[(1-methylcyclopropyl)sulfonyl]carbamoyl}cyclopropyl]-14-methoxy-9-methyl-3,6-dioxo-1,1a,3,4,5,6,9,10,18,19,20,21,22,22a-tetradecahydro-8H-7,10-methanocyclopropa[18,19][1,10,3,6]dioxadiazacyclononadecino[11,12-b]quinoxaline-8-carboxamide

Step 1. Preparation of Example 25: To a suspension of acid 18-7 (30.3mg, 0.0532 mmol) and Intermediate A8 (28.3 mg, 0.0887 mmol) in MeCN (0.5mL) was added DIPEA (60 μL, 0.34 mmol). To the resulting solution wasadded HATU (32.4 mg, 0.0852 mmol). The reaction was stirred at rt for2.5 h and was diluted with EtOAc (30 mL), 0.2 M aqueous HCl (20 mL), andbrine (10 mL). The phases were separated and the aqueous phase wasextracted with EtOAc (30 mL). The combined organic phase was dried overNa₂SO₄, filtered, and concentrated to afford a crude residue that wasdissolved in CH₂Cl₂ and adsorbed onto 2 g silica gel. Purification bysilica gel chromatography (15% to 55% acetone in hexanes) provided aresidue that was lyophilized from water and MeCN to provide Example 25as a white amorphous solid (33.9 mg). Analytic HPLC RetTime: 8.66 min.LCMS-ESI (m/z): [M+H]⁺ calcd for C₄₀H₅₅F₂N₆O₉S: 833.4. found: 833.4. ¹HNMR (400 MHz, CDCl₃) δ 9.62 (s, 1H), 7.82 (d, J=9.1 Hz, 1H), 7.18 (dd,J=9.1, 2.8 Hz, 1H), 7.08 (d, J=2.7 Hz, 1H), 6.64 (s, 1H), 6.04-5.66 (m,1H), 5.54 (d, J=4.0 Hz, 1H), 5.47 (d, J=10.0 Hz, 1H), 4.50-4.38 (m, 3H),4.11 (dd, J=11.8, 4.2 Hz, 1H), 3.93 (s, 3H), 3.82-3.71 (m, 1H),2.98-2.68 (m, 4H), 2.27-2.11 (m, 2H), 1.96-1.41 (m, 12H), 1.32 (dd,J=9.6, 5.4 Hz, 1H), 1.15 (d, J=7.4 Hz, 3H), 1.10 (s, 9H), 1.05-0.64 (m,6H), 0.51-0.42 (m, 1H).

Example 26 Preparation of(1R,4S,4aR,8S,11S,12S,13R,25aR)-8-tert-butyl-N-[(1R,2R)-1-[(cyclopropylsulfonyl)carbamoyl]-2-(difluoromethyl)cyclopropyl]-17-methoxy-12-methyl-6,9-dioxo-2,3,4,4a,6,7,8,9,12,13,21,22,23,24,25,25a-hexadecahydro-1H,11H-1,4:10,13-dimethanoquinoxalino[2,3-k][1,10,3,6]benzodioxadiazacyclononadecine-11-carboxamide

Step 1. Preparation of 26-2: To a solution of 26-1 (311 mg, 0.710 mmol;prepared similarly to 18-1 of Example 18 substituting Intermediate B2for Intermediate B1 in step 1) in dioxane (1.8 mL) was added 4 M HCl indioxane (1.8 mL, 7.2 mmol). The reaction was stirred for 15.5 h at rtand was then concentrated under reduced pressure to give 26-2 as a whiteamorphous solid that was used without further purification in thefollowing step. LCMS-ESI⁺ (m/z): [M+H]⁺ calcd for C₁₆H₁₉ClN₃O₄: 352.1.found: 352.2.

Steps 2 and 3. Preparation of diastereomeric mixture 26-3 and 26-4:Amine hydrochloride 26-2 (0.710 mmol) was dissolved along with 1:1mixture of Intermediate mixture D9 and D10 (266 mg, 0.788 mmol) andDIPEA (600 μL, 3.4 mmol) in DMF (4.5 mL). HATU (360 mg, 0.95 mmol) wasadded in one portion. The reaction was stirred 1.75 h at rt and wasdiluted with saturated aqueous NaHCO₃ (20 mL), water (10 mL) and EtOAc(30 mL). The phases were separated and the organic phase was washedtwice with a mixture of water (30 mL) and brine (5 mL). The organicphase was dried over anhydrous Na₂SO₄, filtered and concentrated to acrude residue that was purified by silica gel chromatography (10% to 30%EtOAc in hexanes) to provide a colorless residue (380 mg; LCMS-ESI(m/z): [M+H]⁺ calcd for C₃₅H₄₈ClN₄O₇: 671.3. found: 671.6). A stirredheterogeneous mixture of this residue, PdCl₂(dppf)*CH₂Cl₂ (35 mg, 0.043mmol) and potassium vinyltrifluoroborate (156 mg, 1.16 mmol) in EtOH (7mL) was sparged with argon for several minutes. Triethylamine (170 μL,1.2 mmol) was added and the mixture was heated to 70° C. for 55 min. Thereaction mixture was cooled to ambient temperature, diluted with EtOAc(40 mL), and washed with water (30 mL). The organics were dried overanhydrous Na₂SO₄, filtered and concentrated to afford a residue that waspurified by silica gel chromatography (15% to 30% EtOAc in hexanes) toafford diastereomeric mixture 26-3 and 26-4 as a yellow residue (277mg). LCMS-ESI (m/z): [M+H]⁺ calcd for C₃₇H₅₁N₄O₇: 663.4. found: 663.3.

Step 4. Preparation of 26-5: Diastereomeric mixture 26-3 and 26-4 (277mg, 0.419 mmol) was dissolved in DCE (140 mL) and the solution wassparged with Ar for 15 min. Zhan 1B catalyst (37 mg, 0.050 mmol, Strem)was added and the resulting solution was stirred at 85° C. under Ar for1.5 h. The reaction mixture was then concentrated and purified by silicagel chromatography (20% to 50% EtOAc in hexanes) to afford 26-5 as anamorphous residue (105 mg). LCMS-ESI⁺ (m/z): [M+H]⁺ calcd forC₃₅H₄₇N₄O₇: 635.3. found: 635.3.

Steps 5 and 6. Preparation of 26-6: To a solution of 26-5 (105 mg, 0.165mmol) in 1:1 EtOAc:EtOH (4 mL) was added Pd/C (10 wt % Pd, 43 mg). Thereaction vessel was purged twice with H₂ and was stirred at rt under 1atm H₂ for 1 h. The reaction mixture was filtered through a pad ofCelite and concentrated to afford a crude residue (106 mg; LCMS-ESI(m/z): [M+H]⁺ calcd for C₃₅H₄₉N₄O₇: 637.4. found: 637.3). This residuewas then dissolved in THF (0.8 mL). MeOH (0.4 mL), water (0.4 mL) andLiOH*H₂O (67 mg, 1.6 mmol) were added and the mixture was stirred at 45°C. for 14.5 h. The reaction was quenched dropwise with 1 N aqueous HCl(1.3 mL) and was diluted with CH₂Cl₂ (30 mL) and 1 N aqueous HCl (20mL). The phases were separated, and the aqueous phase was extracted withCH₂Cl₂ (30 mL). The combined organic phase was dried over MgSO₄,filtered and concentrated to afford 26-6 as a residue (93.8 mg) that wasused directly in Step 7. LCMS-ESI (m/z): [M+H]⁺ calcd for C₃₄H₄₇N₄O₇:623.3. found: 623.3.

Step 7. Preparation of Example 26: To a suspension of acid 26-6 (93.8mg, 0.151 mmol) and Intermediate A9 (58 mg, 0.20 mmol) in MeCN was addedDIPEA (120 μL, 0.69 mmol). To the resulting solution was added HATU(73.5 mg, 0.193 mmol). The reaction was stirred at rt for 100 min and anadditional portion of Intermediate A9 (6 mg, 0.02 mmol) was added. Afteran additional 30 min, additional Intermediate A9 (9 mg, 0.03 mmol), HATU(9 mg, 0.02 mmol) and DIPEA (10 μL, 0.06 mmol) were added. The reactionwas stirred for an additional 50 min and was diluted with EtOAc (25 mL),0.2 M aqueous HCl (20 mL) and brine (10 mL). The phases were separatedand the aqueous phase was extracted with EtOAc (25 mL). The combinedorganic phase was dried over Na₂SO₄, filtered, and concentrated toafford a crude residue. Purification by silica gel chromatography (25%to 40% acetone in hexanes) provided an amorphous residue that waslyophilized from water and MeCN to provide Example 26 as a whiteamorphous solid (113 mg). Analytic HPLC RetTime: 9.19 min. LCMS-ESI⁺(m/z): [M+H]⁺ calcd for C₄₂H₅₇F₂N₆O₉S: 859.4. found: 859.2. ¹H NMR (400MHz, CDCl₃) δ 10.02 (s, 1H), 7.80 (d, J=9.1 Hz, 1H), 7.21-7.15 (m, 2H),7.07 (d, J=2.7 Hz, 1H), 6.13-5.79 (m, 1H), 5.63 (d, J=10.1 Hz, 1H),5.50-5.45 (m, 1H), 4.51 (d, J=10.1 Hz, 1H), 4.44 (d, J=7.4 Hz, 1H), 4.25(s, 1H), 4.18-4.12 (m, 2H), 3.93 (s, 3H), 3.02-2.77 (m, 3H), 2.66-2.57(m, 1H), 2.18-0.90 (m, 36H).

Example 27 Preparation of(3aR,7S,10S,11S,12R,24aR)-7-tert-butyl-N-[(1R,2R)-2-(difluoromethyl)-1-{[(1-methylcyclopropyl)sulfonyl]carbamoyl}cyclopropyl]-16-methoxy-11-methyl-5,8-dioxo-1,2,3,3a,5,6,7,8,11,12,20,21,22,23,24,24a-hexadecahydro-10H-9,12-methanocyclopenta[18,19][1,10,3,6]dioxadiazacyclononadecino[11,12-b]quinoxaline-10-carboxamide

Step 1. Preparation of 27-1: Amine hydrochloride 26-2 (217 mg, 0.504mmol), was treated with BEP (207 mg, 0.756 mmol), Intermediate 05 (283mg, 0.909 mmol), EtOAc (9 mL), NMP (1 mL) and DIPEA (0.44 m, 2.5 mmol),then heated to 50° C. After 1.5 h, the reaction mixture was diluted withEtOAc. The organic solution was washed successively with saturatedaqueous NaHCO₃ and brine, then dried over MgSO₄, filtered andconcentrated under reduced pressure. The residue was purified by silicagel chromatography (9% to 40% EtOAc/Hex) to afford amide 27-1 (235 mg).LCMS-ESI (m/z): [M+H]⁺ calcd for C₃₆H₅₂ClN₄O₇: 687.35. found: 688.13.

Step 2. Preparation of 27-2: Amide 27-1 (235 mg, 0.342 mmol) was treatedwith potassium vinyltrifluoroborate (69 mg, 0.513 mmol), Pd(dppf)Cl₂*DCM(28 mg, 0.0342 mmol), EtOH (3.4 mL) and TEA (0.072 mL, 0.513 mmol), thenheated to reflux. After 50 min, the reaction mixture was diluted withEtOAc and washed with H₂O and brine. The organics were dried over MgSO₄,filtered and concentrated under reduced pressure. The residue waspurified by silica gel chromatography (9% to 40% EtOAc/Hex) to affordvinyl quinoxaline 27-2 (219 mg). LCMS-ESI (m/z): [M+H]⁺ calcd forC₃₈H₅₅N₄O₇: 679.41. found: 679.49.

Steps 3 and 4. Preparation of 27-3: Vinyl quinoxaline 27-2 (219 mg,0.323 mmol) was suspended in DCE (65 mL) and treated with Zhan 1Bcatalyst (41 mg, 0.065 mmol, Strem). The suspension was deoxygenatedwith bubbling N₂ for 17 min, then heated to reflux for 90 min. Thereaction mixture was then filtered over Celite and concentrated underreduced pressure. The crude residue was purified by silica gelchromatography (15% to 50% EtOAc/Hex) to afford the desired macrocycle(165 mg; LCMS-ESI⁺ (m/z): [M+H]⁺ calcd for C₃₆H₅₁N₄O₇: 651.38. found:651.40). The macrocyclic product of step 3 was dissolved in EtOH (10 mL)and EtOAc (2 mL) and treated with 10 wt % Pd/C (95 mg). Hydrogen from aballoon was bubbled through the suspension for 1 min and the mixture wasstirred under H₂ (1 atm) for an additional 1.5 h. The reaction mixturewas filtered over Celite and concentrated under reduced pressure toafford the desired macrocycle 27-3 which was carried on without furtherpurification. LCMS-ESI⁺ (m/z): [M+H]⁺ calcd for C₃₆H₅₃N₄O₇: 653.39.found: 653.32.

Step 5. Preparation of 27-4: The crude product of step 4 was dissolvedin DCM and treated with TMSOTf (0.23 mL, 1.3 mmol). After stirring at rtfor 1 h 15 min, the reaction mixture was concentrated under reducedpressure. The residue was redissolved in DCM and added by pipette to aseparatory funnel containing 1 M aqueous NaOH. The mixture was agitatedfor 1 min, then acidified to pH 1-2 with 10% aqueous HCl. The aqueouslayer was extracted three times with DCM and combined organics driedover MgSO₄, filtered and concentrated under reduced pressure. The crudematerial was purified by silica gel chromatography to afford carboxylicacid 27-4 (119 mg). LCMS-ESI (m/z): [M+H]⁺ calcd for C₃₂H₄₅N₄O₇: 597.33.found: 597.40.

Step 6. Preparation of Example 27: Carboxylic acid 27-4 (105 mg, 0.177mmol) and Intermediate A10 (65 mg, 0.212 mmol) were treated with TBTU(68 mg, 0.212 mmol), DMAP (26 mg, 0.212 mmol), DCM (1.8 mL) and DIPEA(0.31 mL, 1.8 mmol). The reaction mixture was stirred at rt for 30 min,then more amine A10 (40 mg, 0.131 mmol) was added and the reactionmixture was heated to reflux. After an additional 1.25 h, the mixturewas concentrated under reduced pressure. The crude residue was purifiedby HPLC to afford Example 27 (80 mg) in approximately 90% purity as aTFA salt. Analytic HPLC RetTime: 9.06 min. LCMS-ESI (m/z): [M+H]⁺ calcdfor C₄₁H₅₇F₂N₆O₉S: 847.39. found: 847.69. ¹H NMR (400 MHz, CD₃OD) δ 9.23(s, 1H), 7.87-7.72 (m, 1H), 7.31-7.14 (m, 2H), 5.84 (td, J=55.6, 6.5 Hz,1H), 5.58 (d, J=22.6 Hz, 1H), 4.94-4.81 (m, 1H), 4.37 (d, J=15.8 Hz,1H), 4.29-4.10 (m, 2H), 3.94 (s, 3H), 3.01 (ddd, J=15.1, 9.9, 5.3 Hz,1H), 2.84 (p, J=7.4 Hz, 1H), 2.75 (ddd, J=13.3, 10.2, 6.0 Hz, 1H), 2.03(d, J=9.0 Hz, 2H), 1.97-1.74 (m, 4H), 1.73-1.55 (m, 6H), 1.53 (s, 3H),1.48-1.21 (m, 8H), 1.19-1.02 (m, 14H), 0.99-0.80 (m, 2H).

Example 28 Preparation of(3aR,7S,10S,11S,12R,24aR)-7-tert-butyl-N-[(1R,2R)-1-[(cyclopropylsulfonyl)carbamoyl]-2-(difluoromethyl)cyclopropyl]-16-methoxy-11-methyl-5,8-dioxo-1,2,3,3a,5,6,7,8,11,12,20,21,22,23,24,24a-hexadecahydro-10H-9,12-methanocyclopenta[18,19][1,10,3,6]dioxadiazacyclononadecino[11,12-b]quinoxaline-10-carboxamide

Step 1. Carboxylic acid 27-4 (20 mg, 0.034 mmol) and Intermediate A9 (35mg, 0.12 mmol) were treated with TBTU (22 mg, 0.067 mmol), DMAP (8 mg,0.07 mmol), DCM (1 mL) and DIPEA (0.117 mL, 0.674 mmol). The reactionmixture was stirred at rt for 15 h, then concentrated under reducedpressure. The crude residue was purified by HPLC to afford Example 28(22 mg) in approximately 90% purity as a TFA salt. Analytic HPLCRetTime: 8.90 min. LCMS-ESI⁺ (m/z): [M+H]⁺ calcd for C₄₀H₅₅F₂N₆O₉S:833.37. found: 833.61. ¹H NMR (400 MHz, CD₃OD) δ 9.23 (s, 1H), 7.79 (d,J=8.8 Hz, 1H), 7.34-7.10 (m, 2H), 5.86 (td, J=55.8, 6.5 Hz, 1H), 5.61(s, 1H), 4.54 (t, J=9.7 Hz, 1H), 4.36 (d, J=16.5 Hz, 1H), 4.28-4.07 (m,2H), 3.95 (d, J=17.8 Hz, 3H), 3.08-2.91 (m, 2H), 2.90-2.79 (m, 1H), 2.73(ddd, J=13.3, 10.3, 6.0 Hz, 1H), 2.04 (s, 2H), 1.97-1.74 (m, 4H), 1.64(ddd, J=18.7, 11.6, 4.0 Hz, 4H), 1.49-1.19 (m, 11H), 1.18-0.94 (m, 14H),0.94-0.80 (m, 1H).

Example 29 Preparation of(1aR,5S,8S,9S,10R,22aR)-5-tert-butyl-N-[(1R,2R)-2-(difluoromethyl)-1-{[(1-methylcyclopropyl)sulfonyl]carbamoyl}cyclopropyl]-14-methoxy-3,6-dioxo-9-propyl-1,1a,3,4,5,6,9,10,18,19,20,21,22,22a-tetradecahydro-8H-7,10-methanocyclopropa[18,19][1,10,3,6]dioxadiazacyclononadecino[11,12-b]quinoxaline-8-carboxamide

Step 1. Preparation of 29-1: To a solution of Intermediate B5 (188 mg,0.57 mmol) and Intermediate E1 (233 mg, 0.86 mmol) in MeCN (2.85 mL) wasadded cesium carbonate (280 mg, 9.18 mmol) at rt under an argonatmosphere. After 19 h, the reaction mixture was then filtered through apad of Celite and the filtrate concentrated in vacuo. The crude residuewas purified by silica gel chromatography (0-100% ethyl acetate/hexanesgradient) to afford substituted quinoxaline 29-1 (240 mg) as a colorlessoil. LCMS-ESI (m/z): [M+H]⁺ calcd for C₂₆H₃₇ClN₃O₆: 522.2. found: 522.3.

Step 2. Preparation of 29-2: To a solution 29-1 (240 mg, 0.46 mmol) indioxane (1 mL) was added 4 M hydrochloric acid in dioxane (4 mL, 1 mmol)and the reaction stirred at rt. After 15 h, the reaction mixture wasconcentrated in vacuo to afford amine hydrochloride 29-2 (200 mg) as anoff white solid, which was used directly in the next step withoutfurther purification. LCMS-ESI (m/z): [M+H]⁺ calcd for C₂₁H₂₉ClN₃O₄:422.2. found: 422.2.

Step 3. Preparation of 29-3: To a solution of 29-2 (200 mg, 0.46 mmol)and Intermediate D1 (170 mg, 0.51 mmol) in MeCN (2.3 mL) was added HATU(192 mg, 0.51 mmol) followed by DIPEA (400 μL, 2.30 mmol) at rt underand argon atmosphere. After 1.5 h, the reaction mixture was concentratedin vacuo, and the crude residue was purified by silica gelchromatography (0-100% ethyl acetate/hexanes gradient) to afford amide29-3 (67 mg) as a colorless oil. LCMS-ESI⁺ (m/z): [M+H]⁺ calcd forC₃₆H₅₂ClN₄O₇: 687.3. found: 687.5.

Step 4. Preparation of 29-4: To a solution of 29-3 (67 mg, 98 μmol), TEA(20 μL, 150 μmol) and potassium vinyltrifluoroborate (19.7 mg, 150 μmol)in EtOH (500 μL) was added PdCl₂(dppf) (8 mg, 9.8 μmol). The reactionmixture was deoxygenated with argon for 10 min and was heated to 78° C.After 40 min, the reaction mixture was allowed to cool to rt and wasconcentrated in vacuo. The crude residue was purified by silica gelchromatography (0-100% ethyl acetate/hexanes gradient) to afford vinylquinoxaline 29-4 (40.2 mg) as a colorless oil. LCMS-ESI (m/z): [M+H]⁺calcd for C₃₈H₅₅N₄O₇: 679.4. found: 679.6.

Step 5. Preparation of 29-5: To a solution of 29-4 (40 mg, 59 μmol) inDCE (11.8 mL) was added Zhan 1B catalyst (4 mg, 6 μmol, Strem) and thereaction mixture was degassed for 10 minutes with argon. The reactionmixture was then heated to 100° C. After 1 h, the reaction mixture wasallowed to cool to rt and was concentrated in vacuo. The crude residuewas purified by silica gel chromatography (0-100% ethyl acetate/hexanesgradient) to afford macrocycle 29-5 (31 mg) as a light yellow oil.LCMS-ESI (m/z): [M+H]⁺ calcd for C₃₆H₅₁N₄O₇: 651.4. found: 651.5.

Step 6. Preparation of 29-6: To a solution of macrocycle 29-5 (31 mg, 47μmol) in ethanol (500 μL) was added Pd/C (10 wt %, 5 mg, 5 μmol) at rtunder an argon atmosphere. The reaction vessel was evacuated andrefilled with 1 atm hydrogen gas (3×) and the reaction mixture wasstirred vigorously at rt. After 1 h, the reaction mixture was dilutedwith ethyl acetate (10 mL) and was filtered through a pad of Celite withethyl acetate washings (3×5 mL). The filtrate was concentrated in vacuoto afford macrocycle 29-6 (31 mg), which was used directly in the nextstep without further purification. LCMS-ESI (m/z): [M+H]⁺ calcd forC₃₆H₅₃N₄O₇: 653.4. found: 653.5.

Step 7. Preparation of 29-7: To a solution of 29-6 (31 mg, 47 μmol) inDCM (0.5 mL) was added TMSOTf (44 μL, 0.25 mmol) at rt under an argonatmosphere. After 25 min, the reaction mixture was concentrated in vacuoand was azeotropically dried from toluene (2×2 mL) to afford carboxylicacid 29-7 (35 mg) as a yellow oil, which was used directly in the nextstep without further purification. LCMS-ESI⁺ (m/z): [M+H]⁺ calcd forC₃₂H₄₅N₄O₇: 597.3. found: 597.4.

Step 8. Preparation of Example 29: To a solution of 29-7 (35 mg, 49μmol) and Intermediate A10 (22 mg, 74 μmol) in MeCN (245 μL) was addedHATU (28 mg, 74 μmol) followed by DIPEA (43 μL, 250 μmol) at rt under anargon atmosphere. After 3 h, the reaction mixture was concentrated invacuo, was purified by preparatory HPLC (Gemini 5u C18 110 Å column,5-100% MeCN/H₂O, 0.1% trifluoroacetic acid modifier) and was lyophilizedto afford Example 29 (22.3 mg) as a white powder TFA salt. Analytic HPLCRetTime: 8.81 min. LCMS-ESI (m/z): [M+H]⁺ calcd for C₄₁H₅₆F₂N₆O₉S:847.4. found: 847.5. ¹H NMR (400 MHz, CDCl₃) δ 9.83 (d, J=9.4 Hz, 1H),7.93 (d, J=9.1 Hz, 1H), 7.36 (d, J=9.1 Hz, 1H), 7.21 (d, J=11.0 Hz, 1H),7.14 (s, 1H), 5.97 (td, J_(H-F)=55 Hz, J=7.2 Hz, 1H), 5.84 (br s, 1H),5.41 (d, J=9.4 Hz, 1H), 4.66-4.34 (m, 3H), 4.13 (app d, J=11.8 Hz, 1H),4.08 (s, 1H), 3.97 (s, 3H), 3.78-3.71 (m, 1H), 3.09-2.65 (m, 5H),2.14-2.04 (m, 1H), 1.87-1.34 (m, 8H), 1.52 (s, 3H), 1.12 (s, 9H),1.08-0.84 (m, 10H), 0.76-0.62 (m, 1H), 0.50 (dd, J=12.6, 6.6 Hz, 1H).

Example 30 Preparation of(1aR,5S,8S,9S,10R,22aR)-5-tert-butyl-N-[(1R,2R)-2-(difluoromethyl)-1-{[(1-methylcyclopropyl)sulfonyl]carbamoyl}cyclopropyl]-14-methoxy-9-(2-methylpropyl)-3,6-dioxo-1,1a,3,4,5,6,9,10,18,19,20,21,22,22a-tetradecahydro-8H-7,10-methanocyclopropa[18,19][1,10,3,6]dioxadiazacyclononadecino[11,12-b]quinoxaline-8-carboxamide

Step 1. Preparation of 30-1: A mixture of Intermediate B6 (139 mg, 0.405mmol), Intermediate E1 (170 mg, 0.625 mmol), and cesium carbonate (203mg, 0.623 mmol) in 3.3 mL of acetonitrile was stirred at roomtemperature under argon overnight. Reaction mixture was filtered overCelite, washing with ethyl acetate, and filtrate was concentrated underreduced pressure. The resulting residue was purified by silica gelchromatography (0-30% ethyl acetate in hexanes) to yield 30-1 (170 mg)as a clear film. LCMS-ESI (m/z): [M+H]⁺ calcd for C₂₇H₃₉ClN₃O₆: 536.24.found: 536.31.

Step 2. Preparation of 30-2: A solution of hydrogen chloride in dioxane(4.0 M, 0.16 mL, 0.64 mmol) was added to a solution of 30-1 (168 mg,0.314 mmol) in 3.3 mL of dioxane at room temperature. After thirtyminutes, an additional 4 equivalents of HCl was added and mixture wasstirred overnight. An additional 25 equivalents of HCl was then added.After thirty minutes, an additional 19 equivalents of HCl was added.After one hour, an additional 29 equivalents of HCl was added. Afterthirty minutes, reaction mixture was concentrated under reduced pressureto yield 30-2 (148 mg, 85% purity), which was used in the next stepwithout further purification. LCMS-ESI (m/z): [M+H]⁺ calcd forC₂₂H₃₁ClN₃O₄: 436.19. found: 436.25.

Step 3. Preparation of 30-3: HATU (144 mg, 0.379 mmol, Oakwood) andDIPEA (0.28 mL, 1.58 mmol) were added to a mixture of 30-2 (148 mg,0.315 mmol) and Intermediate D1 (99 mg, 0.348 mmol) in 3.5 mL of DMFunder argon. After stirring overnight, reaction mixture was poured intowater and extracted with ethyl acetate (3×). Combined organics werewashed with water and brine, dried (MgSO₄), filtered, and concentratedunder reduced pressure. The resulting residue was purified by silica gelchromatography (0-50% ethyl acetate in hexanes) to yield 30-3 (136 mg)as a white solid. LCMS-ESI (m/z): [M+H]⁺ calcd for C₃₇H₅₄ClN₄O₇: 701.36.found: 701.47.

Step 4. Preparation of 30-4: Pd(dppf)₂Cl₂*CH₂Cl₂ (35 mg, 0.043 mmol) wasadded to a degassed mixture of 30-3 (135 mg, 0.193 mmol), potassiumvinyltrifluoroborate (41 mg, 0.306 mmol), and triethylamine (0.040 mL,0.289 mmol) in 2.1 mL of ethanol at room temperature. Reaction mixturewas heated at 78° C. under argon for 45 minutes. After cooling to roomtemperature, reaction mixture was poured into water and extracted withethyl acetate (three times). Combined organics were washed with waterand brine, dried (MgSO₄), filtered, and concentrated under reducedpressure to yield 30-4 (133 mg), which was used in the next step withoutfurther purification. LCMS-ESI (m/z): [M+H]⁺ calcd for C₃₉H₅₇N₄O₇:693.41. found: 693.48.

Step 5. Preparation of 30-5: A mixture of 30-4 (133 mg, 0.192 mmol) andZhan 1B catalyst (16 mg, 0.022 mmol, Strem) in 38 mL of DCE wasdeoxygenated under argon for 25 minutes. The mixture was then heated at95° C. for 50 minutes. After cooling to room temperature, reactionmixture was concentrated under reduced pressure. The resulting residuewas purified by silica gel chromatography (0-50% ethyl acetate inhexanes) to yield 30-5 (70 mg) as a light yellow film. LCMS-ESI (m/z):[M+H]⁺ calcd for C₃₇H₅₃N₄O₇: 665.38. found: 665.50.

Step 6. Preparation of 30-6: Palladium on carbon (10 wt % Pd, 22 mg,0.0208 mmol) was added to a solution of 30-5 (69 mg, 0.104 mmol) in 3 mLof ethanol. Mixture was then stirred under an atmosphere of hydrogen for1 hour and then was filtered over Celite, washing with ethyl acetate.Filtrate was concentrated under reduced pressure to yield 30-6 (64 mg)as a light yellow-brown solid film, which was used in the next stepwithout further purification. LCMS-ESI⁺ (m/z): [M+H]⁺ calcd forC₃₇H₅₅N₄O₇: 667.40. found: 667.43.

Step 7. Preparation of 30-7: TMSOTf (0.050 mL, 0.274 mmol) was addeddropwise to a solution of 30-6 (30 mg, 0.045 mmol) in 1.2 mL ofdichloromethane under argon at room temperature. After 45 minutes,reaction mixture was concentrated under reduced pressure. The resultingfilm was taken up in 5 mL of toluene and concentrated under reducedpressure. This process was repeated a second time to yield 30-7 (27 mg),which was used in the next step without further purification. LCMS-ESI⁺(m/z): [M+H]⁺ calcd for C₃₃H₄₇N₄O₇: 611.34. found: 611.41.

Step 8. Preparation of Example 30: HATU (28 mg, 0.074 mmol, Oakwood) andDIPEA (0.050 mL, 0.281 mmol) were added to a mixture of 30-7 (27 mg,0.045 mmol) and Intermediate A10 (22 mg, 0.072 mmol) in 2.2 mL ofacetonitrile under argon. After stirring overnight, reaction mixture waspoured into water and extracted with ethyl acetate (3×). Combinedorganics were washed with water and brine, dried (MgSO₄), filtered, andconcentrated under reduced pressure. The resulting residue was purifiedby silica gel chromatography (0-50% ethyl acetate in hexanes) andreverse phase prep HPLC (15-100% acetonitrile in water, with 0.1%trifluoroacetic acid buffer) to yield the trifluoroacetic acid salt ofExample 30 (18 mg) as a light yellow solid, after lyophilization.Analytic HPLC RetTime: 8.96 min. LCMS-ESI (m/z): [M+H]⁺ calcd forC₄₂H₅₉F₂N₆O₉S: 861.40. found: 861.30. ¹H NMR (400 MHz, CD₃OD): δ 9.17(s, 1H), 7.80 (d, J=8.8 Hz, 1H), 7.23 (dd, J=8.8, 2.8 Hz, 1H), 7.14 (d,J=2.8 Hz, 1H), 5.81 (td, J_(H-F)=56 Hz, J=7.6 Hz, 1H); 5.77 (d, J=3.2Hz, 1H), 4.55 (d, J=7.2 Hz, 1H), 4.39 (t, J=5.6 Hz, 2H), 4.16 (dd,J=11.8, 4 Hz, 1H), 3.91 (s, 3H), 3.79-3.71 (m, 1H), 2.98-2.90 (m, 1H),2.84 (dd, J=12.6, 4.8 Hz, 1H), 2.79-2.72 (m, 1H), 2.06-1.91 (m, 3H),1.77 (m, 3H), 1.64-1.44 (m, 6H), 1.51 (s, 3H), 1.44-1.32 (m, 3H),1.15-1.07 (m, 1H), 1.10 (s, 9H), 1.06-0.96 (m, 3H), 1.04-1.01 (m, 6H),0.93-0.89 (m, 2H), 0.79-0.68 (m, 1H), 0.52-0.47 (m, 1H).

Example 31 Preparation of(1aR,5S,8S,9S,10R,22aR)-5-tert-butyl-9-cyclopropyl-N-[(1R,2R)-2-(difluoromethyl)-1-{[(1-methylcyclopropyl)sulfonyl]carbamoyl}cyclopropyl]-14-methoxy-3,6-dioxo-1,1a,3,4,5,6,9,10,18,19,20,21,22,22a-tetradecahydro-8H-7,10-methanocyclopropa[18,19][1,10,3,6]dioxadiazacyclononadecino[11,12-b]quinoxaline-8-carboxamide

Step 1. Preparation of 31-1: An unpurified sample of Intermediate B3 wastreated with Intermediate E1 (217 mg, 0.797 mmol), MeCN (5.7 mL) andCs₂CO₃ (371 mg, 1.14 mmol). After stirring at rt for 17 h, the reactionmixture was filtered over Celite and concentrated under reducedpressure. The crude residue was purified by silica gel chromatography(20% to 40% EtOAc/Hex) to afford quinoxaline 31-1 (143 mg). LCMS-ESI(m/z): [M-Boc+2H]⁺ calcd for C₁₈H₂₁ClN₃O₄: 378.12. found: 378.59.

Step 2. Preparation of 31-2: Quinoxaline 31-1 (143 mg, 0.299 mmol) wasdissolved in DCM (10 mL) and treated with HCl (4.0 M in dioxane, 5 mL,20.0 mmol). After stirring for 2 h at rt, the reaction mixture wasconcentrated and the crude 31-2 was carried on without furtherpurification.

Step 3. Preparation of 31-3: The crude amine hydrochloride 31-2 wastreated with BEP (115 mg, 0.419 mmol), Intermediate D1 (120 mg, 0.423mmol), EtOAc (9 mL), NMP (1 mL) and DIPEA (0.37 mL, 2.1 mmol), thenheated to 50° C. After 1.5 h, the reaction mixture was diluted withEt₂O. The organic solution was washed successively with saturatedaqueous NaHCO₃ and brine, then dried over MgSO₄, filtered andconcentrated under reduced pressure. The residue was purified by silicagel chromatography (15% to 30% EtOAc/Hex) to afford amide 31-3 (166 mg).LCMS-ESI (m/z): [M+H]⁺ calcd for C₃₃H₄₄ClN₄O₇: 643.29. found: 643.48.

Step 4. Preparation of 31-4: Amide 31-3 (166 mg, 0.258 mmol) was treatedwith potassium vinyltrifluoroborate (52 mg, 0.387 mmol), Pd(dppf)Cl₂*DCM(21 mg, 0.0258 mmol), EtOH (2.6 mL) and TEA (0.054 mL), then heated toreflux. After 50 min, the reaction mixture was diluted with EtOAc andwashed with H₂O and brine. The organics were dried over MgSO₄, filteredand concentrated under reduced pressure. The residue was purified bysilica gel chromatography (15% to 40% EtOAc/Hex) to afford vinylquinoxaline 31-4 (145 mg). LCMS-ESI⁺ (m/z): [M+H]⁺ calcd for C₃₅H₄₇N₄O₇:635.34. found: 635.58.

Steps 5 and 6. Preparation of 31-5: Vinyl quinoxaline 31-4 (145 mg,0.228 mmol) was suspended in DCE (46 mL) and treated with Zhan 1Bcatalyst (33 mg, 0.0456 mmol, Strem). The suspension was deoxygenatedwith bubbling N₂ for 22 min, then heated to reflux for 50 min. Thereaction mixture was then filtered over Celite and concentrated underreduced pressure. The crude residue was purified by silica gelchromatography (25% to 35% EtOAc/Hex) to afford the desired macrocycle(54 mg; LCMS-ESI⁺ (m/z): [M+H]⁺ calcd for C₃₃H₄₃N₄O₇: 607.31. found:607.67). The macrocyclic product of step 5 was dissolved in EtOH (10 mL)and treated with 10% Pd/C (45 mg). Hydrogen from a balloon was bubbledthrough the suspension for 1 min and hydrogenation (1 atm) was continuedfor an additional 1.5 h. The reaction mixture was filtered over Celiteand concentrated under reduced pressure to afford the desired macrocycle31-5 which was carried on without further purification. LCMS-ESI (m/z):[M+H]⁺ calcd for C₃₃H₄₅N₄O₇: 609.33. found: 609.95.

Step 7. Preparation of 31-6: The crude product 31-5 was dissolved in THFand treated with LiOH (1.0 M in H₂O, 5 mL, 5 mmol). After stirring at rtfor 3 d, the reaction mixture was heated to reflux for 20 h. The mixturewas then poured into H₂O and acidified to pH ˜1-2 with 10% HCl. Theaqueous layer was extracted three times with DCM. The combined organicswere dried over MgSO₄, filtered and concentrated under reduced pressure.The crude material was purified by silica gel chromatography (80% to100% EtOAc/Hex) to afford carboxylic acid 31-6 (24 mg). LCMS-ESI⁺ (m/z):[M+H]⁺ calcd for C₃₂H₄₃N₄O₇: 595.31. found: 595.12.

Step 8. Preparation of Example 31: Carboxylic acid 31-6 (24 mg, 0.040mmol) and Intermediate A10 (25 mg, 0.081 mmol) were treated with TBTU(23 mg, 0.081 mmol), DMAP (10 mg, 0.081 mmol), DCM (2 mL) and DIPEA(0.070 mL, 0.40 mmol). The reaction mixture was stirred at rt for 15 hthen concentrated under reduced pressure. The crude residue was purifiedby HPLC to afford Example 31 (13 mg, 34%) in approximately 90% purity asa TFA salt. Analytic HPLC RetTime: 8.92 min. LCMS-ESI⁺ (m/z): [M+H]⁺calcd for C₄₁H₅₅F₂N₆O₉S: 845.37. found: 845.67. ¹H NMR (400 MHz, CD₃OD)δ 9.13 (s, 1H), 7.79 (d, J=9.1 Hz, 1H), 7.23 (dd, J=9.1, 2.7 Hz, 1H),7.13 (d, J=2.7 Hz, 1H), 6.05-5.65 (m, 2H), 4.55 (d, J=7.0 Hz, 1H), 4.47(d, J=11.7 Hz, 2H), 4.27 (dd, J=12.0, 3.7 Hz, 1H), 3.94 (s, 3H), 3.78(dd, J=6.8, 2.8 Hz, 1H), 2.99-2.86 (m, 1H), 2.80 (td, J=13.2, 4.1 Hz,1H), 1.98 (d, J=28.8 Hz, 2H), 1.92-1.67 (m, 4H), 1.65-1.41 (m, 10H),1.33 (d, J=27.7 Hz, 3H), 1.20-1.06 (m, 9H), 1.04-0.84 (m, 6H), 0.82-0.62(m, 3H), 0.61-0.41 (m, 2H), 0.06 (dd, J=9.2, 4.9 Hz, 1H).

Example 32 Preparation of(1aR,5S,8S,9S,10R,22aR)-9-benzyl-5-tert-butyl-N-[(1R,2R)-2-(difluoromethyl)-1-{[(1-methylcyclopropyl)sulfonyl]carbamoyl}cyclopropyl]-14-methoxy-3,6-dioxo-1,1a,3,4,5,6,9,10,18,19,20,21,22,22a-tetradecahydro-8H-7,10-methanocyclopropa[18,19][1,10,3,6]dioxadiazacyclononadecino[11,12-b]quinoxaline-8-carboxamide

Step 1. Preparation of 32-1: To a solution of Intermediate B7 (390 mg,1.00 mmol) and Intermediate E1 (272 mg, 1.00 mmol) in MeCN (5 mL) wasadded cesium carbonate (390 mg, 1.00 mmol) at rt under an argonatmosphere. After 24 h, the reaction mixture was diluted with ethylacetate (50 mL). The resulting mixture was washed with saturated aqueoussodium bicarbonate solution (50 mL) and brine (50 mL), was dried overanhydrous sodium sulfate, and was concentrated in vacuo. The cruderesidue was purified by silica gel chromatography (0-100% ethylacetate/hexanes gradient) to afford quinoxaline 32-1 (550 mg) as acolorless oil. LCMS-ESI (m/z): [M+H]⁺ calcd for C₃₀H₃₇ClN₃O₆: 570.2.found: 570.2.

Step 2. Preparation of 32-2: To a solution of 32-1 (549 mg, 0.96 mmol)in dioxane (2 mL) was added 4 M hydrochloric acid in dioxane (2 mL, 1mmol) and the reaction was stirred at rt. After 24 h, the reactionmixture was concentrated in vacuo to afford amine hydrochloride 32-2(461 mg) as an off white solid, which was used directly in the next stepwithout further purification. LCMS-ESI⁺ (m/z): [M+H]⁺ calcd forC₂₅H₂₉ClN₃O₄: 470.2. found: 470.2.

Step 3. Preparation of 32-3: To a solution of 32-2 (461 mg, 0.96 mmol)and Intermediate D1 (369 mg, 1.10 mmol) in MeCN (5 mL) was added HATU(418 mg, 1.10 mmol) followed by DIPEA (869 μL, 5.00 mmol) at rt underand argon atmosphere. After 24 h, the reaction mixture was concentratedin vacuo, and the crude residue was purified by silica gelchromatography (0-100% ethyl acetate/hexanes gradient) to afford 32-3(202.6 mg) as a colorless oil. LCMS-ESI⁺ (m/z): [M+H]⁺ calcd forC₄₀H₅₂ClN₄O₇: 735.3. found: 735.4.

Step 4. Preparation of 32-4: To a solution of 32-3 (202 mg, 276 μmol),TEA (56 μL, 414 μmol) and potassium vinyltrifluoroborate (56 mg, 414μmol) in EtOH (2.76 mL) was added PdCl₂(dppf) (22.5 mg, 27.6 μmol). Thereaction mixture was degassed with argon for 10 min and was heated to78° C. After 1 h, the reaction mixture was allowed to cool to rt and wasconcentrated in vacuo. The crude residue was purified by silica gelchromatography (0-100% ethyl acetate/hexanes gradient) to afford 32-4(163 mg) as a yellow oil. LCMS-ESI⁺ (m/z): [M+H]⁺ calcd for C₄₂H₅₅N₄O₇:727.4. found: 727.5.

Step 5. Preparation of 32-5: To a solution of 32-4 (163 mg, 220 μmol) inDCE (44 mL) was added Zhan 1B catalyst (16 mg, 22 μmol, Strem) and thereaction mixture was degassed for 10 minutes with argon. The reactionmixture was then heated to 100° C. After 45 min, the reaction mixturewas allowed to cool to rt and was concentrated in vacuo. The cruderesidue was purified by silica gel chromatography (0-100% ethylacetate/hexanes gradient) to afford 32-5 (125 mg) as a light yellow oil.LCMS-ESI (m/z): [M+H]⁺ calcd for C₄₀H₅₁N₄O₇: 699.4. found: 699.4.

Step 6. Preparation of 32-6: To a solution of macrocycle 32-5 (124 mg,178 μmol) in ethanol (890 μL) was added Pd/C (10 wt % Pd, 19 mg, 18μmol) at rt under an argon atmosphere. The reaction vessel was evacuatedand refilled with hydrogen gas (3×) and the reaction mixture was stirredvigorously at rt under 1 atm H₂. After 2.5 h, the reaction mixture wasdiluted with ethyl acetate (5 mL) and was filtered through a pad ofCelite with ethyl acetate washings (3×5 mL). The filtrate wasconcentrated in vacuo to afford 32-6 (139 mg), which was used directlyin the next step without further purification. LCMS-ESI (m/z): [M+H]⁺calcd for C₄₀H₅₃N₄O₇: 701.4. found: 701.5.

Steps 7 and 8. Preparation of Example 32: To a solution of 32-6 (124 mg,178 μmol) in DCM (3 mL) was added TFA (2 mL) at rt under an argonatmosphere. After 3 h, the reaction mixture was concentrated in vacuoand was azeotropically dried from toluene (2×2 mL) to afford the desiredcarboxylic acid as a yellow oil, which was used directly in the nextstep without further purification. (126 mg; LCMS-ESI⁺ (m/z): [M+H]⁺calcd for C₃₆H₄₅N₄O₇: 645.3. found: 645.4). To a solution of thiscarboxylic acid (120 mg, 178 μmol) and Intermediate A10 (119 mg, 392μmol) in MeCN (1 mL) was added HATU (151 mg, 392 μmol) followed by DIPEA(155 μL, 890 μmol) at rt under an argon atmosphere. After 30 min, thereaction mixture was concentrated in vacuo, and the crude residue waspurified by silica gel chromatography (0-100% ethyl acetate/hexanesgradient). The fractions containing the desired product were combined,were repurified by preparatory HPLC (Gemini 5u C18 110 Å column, 5-100%MeCN/H₂O, 0.1% trifluoroacetic acid modifier) and were lyophilized toafford the TFA salt of Example 32 (23 mg) as a white powder. AnalyticHPLC RetTime: 8.81 min. LCMS-ESI (m/z): [M+H]⁺ calcd for C₄₅H₅₇F₂N₆O₉S:895.4. found: 895.6. ¹H NMR (400 MHz, CD₃OD) δ 9.24 (s, 1H), 7.73 (d,J=9.1 Hz, 1H), 7.47-7.27 (m, 4H), 7.21-7.12 (m, 1H), 6.65 (d, J=2.9 Hz,1H), 5.83 (td, J_(H-F)=55 Hz, J=7.2 Hz, 1H), 5.77 (br s, 1H), 4.63 (d,J=6.9 Hz, 2H), 4.50-4.28 (m, 3H), 3.93 (s, 2H), 3.79-3.71 (m, 1H),3.11-2.99 (m, 1H), 2.97-2.85 (m, 1H), 2.82-2.61 (m, 3H), 1.92 (br s,2H), 1.82-1.70 (m, 2H), 1.63-1.44 (m, 4H), 1.52 (s, 3H), 1.15 (s, 9H),1.04 (br s, 2H), 1.02-0.96 (m, 2H), 0.95-0.88 (m, 4H), 0.78-0.66 (m,1H), 0.56-0.46 (m, 1H).

Example 33 Preparation of(1aS,2aR,6S,9S,10S,11R,23aR,23bS)-6-tert-butyl-N-[(1S,2R)-1-[(cyclopropylsulfonyl)carbamoyl]-2-(difluoromethyl)cyclopropyl]-15-methoxy-10-methyl-4,7-dioxo-1a,2,2a,4,5,6,7,10,11,19,20,21,22,23,23a,23b-hexadecahydro-1H,9H-8,11-methanocyclopropa[4′,5′]cyclopenta[1′,2′:18,19][1,10,3,6]dioxadiazacyclononadecino[11,12-b]quinoxaline-9-carboxamide

Steps 1 and 2. Preparation of diastereomeric mixture 33-1 and 33-2:Quinoxaline 18-2 (220 mg, 0.56 mmol) was dissolved along with 1:1diastereomer Intermediate mixture D12 and D13 (208 mg, 0.643 mmol) inMeCN (5 mL). DIPEA (280 μL, 1.6 mmol) and HATU (360 mg, 0.95 mmol) wereadded, and the reaction was stirred for 1.25 h at rt. The reaction wasthen diluted with EtOAc (30 mL), saturated aqueous NaHCO₃ (15 mL), H₂O(10 mL), and brine (10 mL). The phases were separated and the aqueousphase was extracted with EtOAc (30 mL). The organic phase was dried overanhydrous Na₂SO₄, filtered and concentrated to a crude residue that wasdissolved in CH₂Cl₂ and adsorbed onto silica gel (5 g). Purification bysilica gel chromatography (10% to 30% EtOAc in hexanes) provided a whitefoam (352 mg; LCMS-ESI (m/z): [M+H]⁺ calcd for C₃₇H₅₂ClN₄O₇: 699.4.found: 699.1). A stirred heterogeneous mixture of this residue,PdCl₂(dppf).CH₂Cl₂ (30.7 mg, 0.0376 mmol) and potassiumvinyltrifluoroborate (135 mg, 1.01 mmol) in EtOH (5 mL) was sparged withargon for several minutes. Triethylamine (160 μL, 1.1 mmol) was addedand the mixture was heated to 75° C. for 1 h. The reaction mixture wascooled to ambient temperature and was diluted with EtOAc (30 mL), H₂O(15 mL) and brine (15 mL). The phases were separated, and the aqueousphase was extracted with EtOAc (30 mL). The organics were dried overanhydrous Na₂SO₄, filtered and concentrated to afford a crude residuethat was dissolved in CH₂Cl₂ and adsorbed onto silica gel (3 g).Purification by silica gel chromatography (10% to 40% EtOAc in hexanes)produced inseparable mixture of 33-1 and 33-2 as a yellow residue (258mg). LCMS-ESI (m/z): [M+H]⁺ calcd for C₃₉H₅₅N₄O₇: 691.4. found: 691.7.

Step 3: Preparation of 33-3: Diastereomeric mixture 33-1 and 33-2 (258mg, 0.373 mmol) was dissolved in DCE (125 mL) and the solution wassparged with Ar for 10 min. Zhan 1B catalyst (41 mg, 0.056 mmol, Strem)was added as a solution in DCE (3.3 mL) and the resulting solution wasstirred at 85° C. under Ar for 105 min. The reaction mixture was thenconcentrated onto 5 g silica gel and was purified by silica gelchromatography (0% to 25% EtOAc in hexanes) to afford macrocycle 33-3 asan amorphous residue (81.9 mg). LCMS-ESI (m/z): [M+H]⁺ calcd forC₃₇H₅₁N₄O₇: 663.4. found: 663.3.

Steps 4 and 5: Preparation of 33-4: To a solution of 33-3 (81.9 mg,0.124 mmol) in 1:1 EtOAc:EtOH (4 mL) was added Pd/C (10 wt % Pd, 19 mg).The reaction vessel was purged twice with H₂ and was stirred at rt under1 atm H₂ for 2.5 h. The reaction mixture was filtered through a pad ofCelite and concentrated to afford a crude residue. This residue wasdissolved in CH₂Cl₂ (1.2 mL) and TMSOTf (90 μL, 0.50 mmol) was added.The mixture was stirred at rt for 4.5 h. The reaction was thenconcentrated in vacuo and dissolved in CH₂Cl₂ (5 mL). 0.2 M aqueous NaOH(5 mL) was added and the biphasic mixture was stirred at rt for 5 min.The mixture was then acidified with 1 M aqueous HCl (20 mL) and wasdiluted with CH₂Cl₂ (20 mL). The phases were separated and the aqueousphase was extracted with CH₂Cl₂ (2×20 mL). The combined organic phasewas dried over MgSO₄, filtered, and concentrated to afford 33-4 as acrude residue (76.1 mg). LCMS-ESI (m/z): [M+H]⁺ calcd for C₃₃H₄₅N₄O₇:609.3. found: 608.9.

Step 6: Preparation of Example 33: To a suspension of acid 33-4 (43 mg,0.072 mmol) and Intermediate A9 (40.9 mg, 0.14 mmol) in MeCN (800 μL)was added DIPEA (100 μL, 0.57 mmol). HATU (37 mg, 0.097 mmol) was addedto the resulting solution, and the reaction was stirred at rt for 15 h.The reaction was then diluted with EtOAc (20 mL), 0.2 M aqueous HCl (10mL) and brine (10 mL). The phases were separated and the aqueous phasewas extracted with EtOAc (20 mL). The combined organic phase was driedover Na₂SO₄, filtered, and concentrated to afford a crude residue. Thisresidue was dissolved in CH₂Cl₂ and was concentrated onto 2 g silicagel. Purification by silica gel chromatography (15% to 55% acetone inhexanes) provided an amorphous residue that was lyophilized from waterand MeCN to provide Example 33 as a white amorphous solid (29.6 mg).Analytic HPLC RetTime: 9.07 min. LCMS-ESI (m/z): [M+H]⁺ calcd forC₄₁H₅₅F₂N₆O₉S: 845.4. found: 845.2. ¹H NMR (400 MHz, CDCl₃) b 10.21 (s,1H), 7.82 (d, J=9.1 Hz, 1H), 7.19 (dd, J=9.1, 2.7 Hz, 1H), 7.09 (d,J=2.7 Hz, 1H), 6.79 (s, 1H), 6.21-5.76 (m, 1H), 5.65 (d, J=3.9 Hz, 1H),5.29 (d, J=9.7 Hz, 1H), 4.99 (d, J=7.5 Hz, 1H), 4.47-4.29 (m, 4H),4.16-4.09 (m, 1H), 3.93 (s, 3H), 2.99-2.85 (m, 2H), 2.80-2.64 (m, 2H),2.24-2.16 (m, 1H), 2.13-2.05 (m, 1H), 2.01-0.95 (m, 29H), 0.56-0.45 (m,1H), 0.45-0.35 (m, 1H).

Example 34 Preparation of(1aR,5S,8S,9S,10R,22aR)-5-tert-butyl-N-{(1R,2R)-1-[(cyclopropylsulfonyl)carbamoyl]-2-ethylcyclopropyl}-9-ethyl-18,18-difluoro-14-methoxy-3,6-dioxo-1,1a,3,4,5,6,9,10,18,19,20,21,22,22a-tetradecahydro-8H-7,10-methanocyclopropa[18,19][1,10,3,6]dioxadiazacyclononadecino[11,12-b]quinoxaline-8-carboxamide

Example 34 was prepared in a similar fashion to Example 17, substitutingIntermediate A3 for Intermediate A10 in Step 7. Example 34 was isolated(5.7 mg) in approximately 95% purity. Analytic HPLC RetTime: 8.81 min.LCMS-ESI (m/z): [M+H]⁺ calcd for C₄₀H₅₅F₂N₆O₉S: 833.4. found: 833.25. ¹HNMR (400 MHz, CDCl₃) δ 10.027 (br s, 1H), 7.98 (d, J=8.8 Hz, 1H), 7.29(dd, J=9.2, 2.8 Hz, 1H), 7.09 (d, J=2.8 Hz, 1H), 6.32 (br s, 1H), 5.92(d, J=3.6 Hz, 1H), 5.30 (d, J=10.0 Hz, 1H), 4.42-4.33 (m, 3H), 4.08 (dd,J=11.6, 4.0 Hz, 1H), 3.96 (s, 3H), 3.65 (m, 1H), 2.93 (m, 1H), 2.51 (m,2H), 2.02 (m, 1H), 1.86-1.40 (m, 11H) 1.34-1.14 (m, 7H), 1.09 (s, 9H),1.10-0.82 (m, 6H), 0.72 (m, 1H), 0.48 (m, 1H).

Example 35 Preparation of(1aR,5S,8S,9S,10R,22aR)-5-tert-butyl-N-[(1R,2S)-2-(2,2-difluoroethyl)-1-{[(1-methylcyclopropyl)sulfonyl]carbamoyl}cyclopropyl]-9-ethyl-18,18-difluoro-14-methoxy-3,6-dioxo-1,1a,3,4,5,6,9,10,18,19,20,21,22,22a-tetradecahydro-8H-7,10-methanocyclopropa[18,19][1,10,3,6]dioxadiazacyclononadecino[11,12-b]quinoxaline-8-carboxamide

Example 35 was prepared in a similar fashion to Example 17, substitutingIntermediate A8 for Intermediate A10 in Step 7. Example 35 was isolated(12.8 mg) in approximately 90% purity. Analytic HPLC RetTime: 8.78 min.LCMS-ESI (m/z): [M+H]⁺ calcd for C₄₁H₅₅F₄N₆O₉S: 883.4. found: 883.2. ¹HNMR (400 MHz, CDCl₃) δ 9.69 (br s, 1H), 7.98 (d, J=9.2 Hz, 1H), 7.29(dd, J=9.2, 2.8 Hz, 1H), 7.09 (d, J=2.8 Hz, 1H), 6.53 (br s, 1H), 5.91(d, J=4.0 Hz, 1H), 5.84 (tt, J_(H-F)=56 Hz, J=3.6 Hz, 1H), 5.33 (d,J=6.4 Hz, 1H), 4.43 (m, 2H), 4.34 (ap d, J=9.6 Hz, 1H), 4.08 (dd,J=11.6, 4.0 Hz, 1H), 3.96 (s, 3H), 3.99-3.94 (m, 1H), 3.68 (m, 1H),2.58-2.52 (m, 3H), 2.20 (m, 2H), 1.82-1.58 (m, 7H) 1.54-1.40 (m, 5H),1.36-1.18 (m, 6H), 1.09 (s, 9H), 1.10-1.00 (m, 1H), 0.85 (m, 2H), 0.69(m, 1H), 0.49 (m, 1H).

Example 36 Preparation of(1aR,5S,8S,9S,10R,21aR)-5-tert-butyl-N-[(1R,2R)-2-(difluoromethyl)-1-{[(1-methylcyclopropyl)sulfonyl]carbamoyl}cyclopropyl]-9-ethyl-14-methoxy-3,6-dioxo-1a,3,4,5,6,9,10,17b,18,18a,19,20,21,21a-tetradecahydro-1H,8H-7,10-methanodicyclopropa[13,14:18,19][1,10,3,6]dioxadiazacyclononadecino[11,12-b]quinoxaline-8-carboxamide

Step 1. Preparation of 36-1: To a solution of trimethylsulfoxoniumiodide (72 mg, 0.32 mmol) in DMSO/THF (1:1, 2 mL) was added sodiumhydride (60%, 12 mg, 0.32 mmol) and stirred at rt for 2 h. Macrocycle1-5 (103 mg, 0.16 mmol) was added dropwise in THF (3 mL). The mixturewas heated to 65° C. and stirred for 16 h. After cooling to rt, themixture was diluted with EtOAc/H₂O, extracted with EtOAc, dried overanhydrous MgSO₄, and concentrated in vacuo. The residue was purified bysilica gel chromatography (0-25% EtOAc/hexanes) to give 36-1 (27 mg) asa residue. LCMS-ESI (m/z): [M+H]⁺ calcd for C₃₆H₅₁N₄O₇: 651.38. found:651.52.

Step 2. Preparation of 36-2: To a solution of 36-1 (26 mg, 0.04 mmol) inDCM (1 mL) was added TMSOTf (0.036 mL, 0.2 mmol) and stirred at rt for 2h. The reaction was pipetted into stirring 1 N NaOH (2 mL). After 10min, the mixture was diluted with DCM and acidified to pH 3 with 1 Naqueous HCl. Following extraction of the aqueous layer with DCM, thecombined organics were dried over anhydrous MgSO₄ and concentrated invacuo. The residue was purified by silica gel chromatography (0-10%EtOAc/MeOH) to give 36-2 (24 mg) as a residue that was used withoutfurther purification. LCMS-ESI (m/z): [M+H]⁺ calcd for C₃₂H₄₃N₄O₇:595.31. found: 595.43.

Step 3. Preparation of Example 36: To a solution of 36-2 (24 mg, 0.041mmol), Intermediate A10 (16 mg, 0.053 mmol), TBTU (19 mg, 0.06 mmol) andDMAP (8 mg, 0.06 mmol) in DCM (2 mL) was added DIPEA (0.021 mL, 0.12mmol) and the reaction was stirred at rt for 16 h. AdditionalIntermediate A10 (16 mg, 0.053 mmol), TBTU (19 mg, 0.06 mmol), DMAP (8mg, 0.06 mmol), and DIPEA (0.021 mL, 0.12 mmol) were added and thereaction was stirred at rt for 4 h. The reaction was quenched withwater, diluted with EtOAc, washed with sat. aqueous NaHCO₃, brine, driedover anhydrous MgSO₄ and concentrated in vacuo. The crude material waspurified by reverse phase HPLC (Gemini, 45-85% MeCN/H₂O+0.1% TFA) andlyophilized to give Example 36 (3 mg) as a TFA salt. Analytic HPLCRetTime: 9.06 min. LCMS-ESI (m/z): [M+H]⁺ calcd for C₄₁H₅₅F₂N₆O₉S:845.37. found: 845.43. ¹H NMR (400 MHz, CD₃OD) δ 9.31 (s, 1H), 7.72 (d,J=10 Hz, 1H), 7.20-7.17 (m, 2H), 5.60-5.82 (m, 2H), 5.51 (s, 1H), 4.72(d, J=7.2 Hz, 1H), 4.43 (d, J=11.6 Hz, 1H), 4.31 (s, 1H), 4.26-4.22 (dd,J=11.6, 4 Hz, 1H), 3.94 (s, 3H), 3.78 (m, 1H), 2.60 (m, 1H), 2.27 (m,1H), 2.04 (s, 3H), 1.68 (m, 3H), 1.59 (m, 2H), 1.54-1.15 (m, 11H), 1.09(s, 9H), 0.95-0.86 (m, 8H), 0.47 (m, 1H).

Example 37 Preparation of(1R,4S,4aR,8S,11S,12S,13R,25aR)-8-tert-butyl-N-[(1R,2R)-2-(difluoromethyl)-1-{[(1-methylcyclopropyl)sulfonyl]carbamoyl}cyclopropyl]-12-ethyl-17-methoxy-6,9-dioxo-2,3,4,4a,6,7,8,9,12,13,21,22,23,24,25,25a-hexadecahydro-1H,11H-1,4:10,13-dimethanoquinoxalino[2,3-k][1,10,3,6]benzodioxadiazacyclononadecine-11-carboxamide

Step 1. Preparation of Example 37: To a solution of 13-6 (76 mg, 0.12mmol), Intermediate A10 (44 mg, 0.14 mmol), HATU (55 mg, 0.14 mmol) andDMAP (21 mg, 0.18 mmol) in DMF (2 mL) was added DIPEA (0.11 mL, 0.6mmol) and the reaction was stirred at rt for 16 h. AdditionalIntermediate A10 (44 mg, 0.14 mmol), HATU (55 mg, 0.14 mmol), DMAP (21mg, 0.18 mmol), followed by DIPEA (0.11 mL, 0.6 mmol) was added and thereaction was stirred at 40° C. for 50 h. The reaction was quenched withwater, diluted with EtOAc, washed with sat. aqueous NaHCO₃, brine, driedover anhydrous MgSO₄ and concentrated in vacuo. The crude material waspurified by reverse phase HPLC (Gemini, 45-85% MeCN/H₂O+0.1% TFA) andlyophilized to give Example 37 (30 mg) as a TFA salt. Analytic HPLCRetTime: 9.44 min. LCMS-ESI (m/z): [M+H]*calcd for C₄₄H₆₁F₂N₆O₉S:887.42. found: 887.50. ¹H NMR (400 MHz, CD₃OD) δ 9.24 (s, 1H), 7.76 (d,J=9.2 Hz, 1H), 7.20 (dd, J=8.8, 2.4 Hz, 1H), 7.12 (m, 1H), 5.95-5.66 (m,2H), 5.43 (s, 1H), 4.51 (d, J=7.6 Hz, 1H), 4.41 (s, 1H), 4.20-4.10 (m,2H), 3.88 (s, 3H), 2.94-2.88 (m, 1H), 2.73-2.63 (m, 2H), 2.11 (br, 2H),2.02-0.83 (m, 41H).

Example 38 Preparation of(1aR,5S,8S,9S,10R,22aR)—N-[(1R,2R)-2-(difluoromethyl)-1-{[(1-methylcyclopropyl)sulfonyl]carbamoyl}cyclopropyl]-14-methoxy-9-methyl-5-(1-methylcyclopentyl)-3,6-dioxo-1,1a,3,4,5,6,9,10,18,19,20,21,22,22a-tetradecahydro-8H-7,10-methanocyclopropa[18,19][1,10,3,6]dioxadiazacyclononadecino[11,12-b]quinoxaline-8-carboxamide

Step 1. Preparation of 38-1: Amine 18-2 (192 mg, 0.487 mmol) was treatedwith BEP (246 mg, 0.898 mmol), Intermediate D14 (278 mg, 0.898 mmol),EtOAc (9 mL), NMP (1 mL) and DIPEA (0.42 mL, 2.4 mmol), then heated to50° C. After 1 h, the reaction mixture was diluted with EtOAc. Theorganic solution was washed successively with sat. aqueous NaHCO₃ andbrine, then dried over MgSO₄, filtered and concentrated in vacuo. Theresidue was purified by silica gel chromatography (15% to 35% EtOAc/Hex)to afford amide 38-1 (264 mg). LCMS-ESI (m/z): [M+H]⁺ calcd forC₃₆H₅₀ClN₄O₇: 685.34. found: 685.82.

Step 2. Preparation of 38-2: Amide 38-1 (264 mg, 0.385 mmol) was treatedwith potassium vinyltrifluoroborate (82 mg, 0.615 mmol), Pd(dppf)Cl₂*DCM(33 mg, 0.041 mmol), EtOH (4.0 mL) and TEA (0.086 mL, 0.62 mmol), thenheated to reflux. After 55 min, the reaction mixture was diluted withEtOAc and washed with H₂O and brine. The organics were dried overanhydrous MgSO₄, filtered and concentrated in vacuo. The residue waspurified by silica gel chromatography (15% to 30% EtOAc/Hex) to affordvinyl quinoxaline 38-2 (168 mg). LCMS-ESI (m/z): [M+H]⁺ calcd forC₃₈H₅₃N₄O₇: 677.39. found: 677.38.

Steps 3 and 4. Preparation of 38-3: Vinyl quinoxaline 38-2 (225 mg,0.332 mmol) was suspended in DCE (66 mL) and treated with Zhan 1Bcatalyst (42 mg, 0.067 mmol, Strem). The suspension was degassed withbubbling N₂ for 28 min, then heated to reflux for 90 min. The reactionmixture was then filtered over Celite and concentrated in vacuo. Thecrude residue was purified by silica gel chromatography (15% to 30%EtOAc/Hex) to afford the desired macrocycle (168 mg; LCMS-ESI (m/z):[M+H]⁺ calcd for C₃₆H₄₉N₄O₇: 649.36. found: 649.33). The macrocycle wasdissolved in EtOH (25 mL) and EtOAc (5 mL) and treated with Pd/C (10 wt% Pd, 95 mg). Hydrogen from a balloon was bubbled through the suspensionfor 1 min the reaction was stirred under an H₂ atmosphere for anadditional 1.5 h. Upon completion, the reaction mixture was filteredover Celite and concentrated in vacuo to afford the desired macrocycle38-3 which was carried on without further purification. LCMS-ESI (m/z):[M+H]⁺ calcd for C₃₆H₅₁N₄O₇: 651.38. found: 651.42.

Step 5. Preparation of 38-4: Unpurified 38-3 from the previous step wasdissolved in DCM (10 mL) and treated with TMSOTf (0.23 mL, 1.3 mmol).After stirring at rt for 1 h 15 min, the reaction mixture wasconcentrated in vacuo. The residue was redissolved in DCM and pipettedinto 1 M aqueous NaOH. The mixture was agitated for 1 min, thenacidified to pH 1-2 with 10% aqueous HCl. The aqueous layer wasextracted three times with DCM and combined organics dried overanhydrous MgSO₄, filtered and concentrated in vacuo. The crude materialwas purified by silica gel chromatography (0% to 20% MeOH/EtOAc) toafford carboxylic acid 38-4 (131 mg). LCMS-ESI (m/z): [M+H]⁺ calcd forC₃₂H₄₃N₄O₇: 595.31. found: 595.29.

Step 6. Preparation of Example 38: Carboxylic acid 38-4 (131 mg, 0.220mmol) and Intermediate A10 (81 mg, 0.264 mmol) were treated with TBTU(85 mg, 0.264 mmol), DMAP (32 mg, 0.264 mmol), DCM (2.6 mL) and DIPEA(0.38 mL, 2.2 mmol). The reaction mixture was stirred at rt for 14 h,then concentrated under reduced pressure. The crude residue was purifiedby HPLC to afford Example 38 (74 mg) in approximately 90% purity as aTFA salt. Analytic HPLC RetTime: 8.93 min. LCMS-ESI⁺ (m/z): [M+H]⁺ calcdfor C₄₁H₅₅F₂N₆O₉S: 845.37. found: 845.57. ¹H NMR (400 MHz, CD₃OD) δ 9.12(s, 1H), 7.77 (d, J=9.2 Hz, 1H), 7.20 (dd, J=9.0 Hz, 2.7 Hz, 1H), 7.16(d, J=2.8 Hz, 1H), 5.81 (td, J=55.9, 6.6 Hz, 1H), 5.59 (d, J=3.5 Hz,1H), 4.52 (d, J=6.8 Hz, 1H), 4.50 (s, 1H), 4.40 (d, J=12.0 Hz, 1H), 4.18(dd, J=11.9 Hz, 3.9 Hz, 1H), 3.93 (s, 3H), 3.74 (m, 1H), 2.97-2.90 (m,1H), 2.85-2.75 (m, 2H), 2.01 (m, 2H), 1.85-1.41 (m, 21H), 1.12 (s, 3H),1.08 (d, J=7.4 Hz, 3H), 0.96 (m, 2H), 0.91 (t, J=4.3 Hz, 2H), 0.70 (m,1H), 0.48 (m, 1H).

Example 39 Preparation of(3aR,7S,10S,11S,12R,24aR)-7-tert-butyl-N-[(1R,2R)-2-(difluoromethyl)-1-{[(1-methylcyclopropyl)sulfonyl]carbamoyl}cyclopropyl]-1-ethyl-16-methoxy-3a-methyl-5,8-dioxo-1,2,3,3a,5,6,7,8,11,12,20,21,22,23,24,24a-hexadecahydro-10H-9,12-methanocyclopenta[18,19][1,10,3,6]dioxadiazacyclononadecino[11,12-b]quinoxaline-10-carboxamide

Step 1. Preparation of 39-1: Quinoxaline ether 1-1 (588.7 mg, 1.159mmol) was dissolved in TFA (5 mL). The solution was stirred at roomtemperature for 3 h. The TFA was removed in vacuo to give the TFA saltof 39-1 (631.2 mg) as a colorless powder. LCMS-ESI⁺ (m/z): [M+H]⁺ calcdfor C₁₆H₁₉C₁N₃O₄: 352.1. found: 352.1.

Step 2. Preparation of 39-2: The TFA salt of 39-1 (631.2 mg, 1.159 mmol)was dissolved in CH₂Cl₂/MeOH (3 mL/3 mL). To the solution was added asolution of TMSCHN₂ (2 M hexane, 3 mL, 5.177 mmol) at rt. The solutionwas stirred for 30 min to produce a suspension that was filtered througha fritted glass funnel to remove solids. The filtrate was concentratedin vacuo to afford a residue that was purified by silica gelchromatography (100% ethyl acetate) to produce methyl ester 39-2 (213.0mg) as colorless crystals. LCMS-ESI (m/z): [M+H]⁺ calcd forC₁₇H₂₁ClN₃O₄: 366.1. found: 366.1.

Step 3. Preparation of 39-3: Intermediate D7 (191.2 mg, 0.587 mmol) andmethyl ester 39-2 (414.1 mg, 1.132 mmol) were treated with HATU (860.0mg, 2.264 mmol) and DIPEA (0.59 mL, 3.396 mmol) in DMF (8 mL) at rt for4 h. The reaction was quenched with H₂O (50 mL) and extracted with EtOAc(50 mL three times). The combined organics were washed with brine (50mL) and dried over anhydrous Na₂SO₄. After removal of drying agent byfiltration, the solvent was removed in vacuo. The residue was purifiedby silica gel chromatography (20% ethyl acetate in hexanes) to give thedesired amide 39-3 (573.9 mg) as colorless oil. LCMS-ESI⁺ (m/z): [M+Na]⁺calcd for C₃₃H₄₉ClN₄NaO₇: 695.3. found: 695.3.

Step 4. Preparation of 39-4: Amide 39-3 (573.9 mg, 0.8524 mmol),potassium trifluorovinylborate (171.3 mg, 1.279 mmol) andPdCl₂dppf.CH₂Cl₂ (62.4 mg, 0.085 mmol) were treated with Et₃N (0.18 mL,1.279 mmol) in EtOH (8 mL) under a nitrogen atmosphere and gentlyrefluxed for 30 min. The reaction was diluted with PhMe (30 mL) and thesolvent was removed in vacuo. The residue was purified by silica gelchromatography (20% ethyl acetate in hexanes) to give the desired vinylquinoxaline 39-4 (542.0 mg, 0.8152 mmol) as an orange foam. LCMS-ESI⁺(m/z): [M+H]⁺ calcd for C₃₇H₅₂N₄NaO₇: 687.4. found: 687.3.

Step 5. Preparation of 39-5: The vinyl quinoxaline 39-4 (542.0 mg,0.8152 mmol) was treated with Zhan 1b catalyst (59.8 mg, 0.08 mmol,Strem) in DCE (41 mL). The mixture was heated at 80° C. for 1 h.Additional Zhan 1b catalyst (59.8 mg, 0.08 mmol, Strem) was added andthe mixture to heat at 80° C. for an additional 30 min. The solvent wasremoved in vacuo and the residue purified by silica gel chromatography(20% ethyl acetate in hexanes) to produce macrocycle 39-5 (401.0 mg,0.6297 mmol) as an orange oil. LCMS-ESI⁺ (m/z): [M+H]⁺ calcd forC₃₅H₄₉N₄O₇: 637.4. found: 637.3.

Step 6. Preparation of 39-6: Macrocycle 39-5 (401.0 mg, 0.6297 mmol) wastaken up in 1,4-dioxane (15 mL) and treated with Pd/C (10% wt Pd, 200.0mg) and MgO (200.0 mg) stirred under an atmosphere of hydrogen. Themixture was stirred at rt for 1 h. The reaction mixture was filteredthrough Celite (5 g) using EtOAc (80 mL). The solvent was removed invacuo to give macrocycle 39-6 (425.3 mg) as a pale orange oil. LCMS-ESI(m/z): [M+H]⁺ calcd for C₃₅H₅₁N₄O₇: 639.4. found: 639.3.

Step 7. Preparation of 39-7: Macrocycle 39-6 (74.8 mg, 0.110 mmol) wastreated with 2 M aqueous LiOH aqueous solution (1.6 mL, 3.15 mmol) inMeOH/THF (4 mL/4 mL) at rt for 8 h, 50° C. for 2 h and then 60° C. for 3h. The mixture was cooled to 0° C. using ice-water bath. To the mixturewas added brine (30 mL). The whole was extracted with CH₂Cl₂ (30 mLthree times). The organic layer was washed with brine (30 mL) and driedover anhydrous Na₂SO₄. After removal of the drying agent by filtration,the solvent was removed in vacuo to give carboxylic acid 39-7 (370.6 mg,0.5932 mmol) as a colorless oil. LCMS-ESI⁺ (m/z): [M+H]⁺ calcd forC₃₄H₄₉N₄O₇: 625.4. found: 625.3.

Step 8. Preparation of Example 39: Carboxylic acid 39-7 (100.0 mg,0.1601 mmol) and Intermediate A10 (73.2 mg, 0.2401 mmol) were treatedwith HATU (91.3 mg, 0.2401 mmol) and DIPEA (0.14 mL, 0.8005 mmol) in DMF(3 mL) at rt for 5 h. The reaction was quenched with H₂O (30 mL) andextracted with EtOAc (30 mL three times). The organic layer was washedwith brine (30 mL) and dried over anhydrous Na₂SO₄. After removal of thedrying agent by filtration, the solvent was removed in vacuo. Theresidue was purified by silica gel chromatography (25 to 100% ethylacetate in hexanes). Fractions containing desired product wereconcentrated in vacuo and the residue further purified by super criticalfluid column chromatography (DAICEL Chiralpak IC 10×250 mm, 18.9 mL/min,35% MeOH, 15 atm, 40° C.) to give Example 39 (80.5 mg, 0.0920 mmol, 57%)as a colorless powder. Analytic HPLC RetTime: 9.35 min. LCMS-ESI⁺ (m/z):[M+H]⁺ calcd for C₄₃H₆₁F₂N₆O₉S: 875.4. found: 875.4. ¹H NMR (300 MHz,CD₃OD) δ 7.81 (d, J=9.6 Hz, 1H), 7.27 (s, 1H), 7.24 (d, J=9.6 Hz, 1H),6.68 (d, J=9.6 Hz, 1H), 5.74-6.30 (m, 3H), 4.73 (d, J=7.2 Hz, 1H), 4.73(d, J=7.2 Hz, 1H), 4.40-4.60 (m, 1H), 4.22 (d, J=9.6 Hz, 1H), 3.95 (s,3H), 3.61 (q, J=7.2 Hz, 2H), 3.16-3.30 (m, 1H), 2.50-2.77 (m, 2H),2.20-0.60 (m, 21H), 1.35 (s, 3H) 1.12 (t, J=7.2 Hz, 3H), 1.18 (s, 3H),1.02 (s, 9H).

Example 40 Preparation of(3aR,7S,10S,11S,12R,24aR)-7-tert-butyl-N-[(1R,2R)-1-[(cyclopropylsulfonyl)carbamoyl]-2-(difluoromethyl)cyclopropyl]-11-ethyl-16-methoxy-3a-methyl-5,8-dioxo-1,2,3,3a,5,6,7,8,11,12,20,21,22,23,24,24a-hexadecahydro-1OH-9,12-methanocyclopenta[18,19][1,10,3,6]dioxadiazacyclononadecino[11,12-b]quinoxaline-10-carboxamide

Example 40 was prepared in a similar fashion to Example 39, substitutingIntermediate A9 for Intermediate A10 in Step 8. Example 40 was isolated(70.9 mg) in approximately 92% purity. Analytic HPLC RetTime: 9.24 min.LCMS-ESI (m/z): [M+H]⁺ calcd for C₄₂H₅₉F₂N₆O₉S: 861.4. found: 861.4. ¹HNMR (300 MHz, CD₃OD) δ 7.80 (d, J=9.6 Hz, 1H), 7.25 (s, 1H), 7.23 (d,J=9.6 Hz, 1H), 6.70 (d, J=9.6 Hz, 1H), 5.60-6.10 (m, 3H), 4.69 (d, J=7.2Hz, 1H), 4.39 (dd, J=12.0, 6.0 Hz, 1H), 4.2 (d, J=9.6 Hz, 1H), 4.03-4.10(m, 1H), 3.94 (s, 3H), 3.12-3.28 (m, 1H), 2.89-3.05 (m, 1H), 2.50-2.76(m, 2H), 2.30-0.80 (m, 19H), 1.36 (s, 3H) 1.25 (t, J=7.2 Hz, 3H), 1.10(s, 3H), 1.04 (s, 9H).

Example 41 Preparation of(3aR,7S,10S,11S,12R,24aR)-7-tert-butyl-N-[(1R,2S)-2-(2,2-difluoroethyl)-1-{[(1-methylcyclopropyl)sulfonyl]carbamoyl}cyclopropyl]-1-ethyl-16-methoxy-3a-methyl-5,8-dioxo-1,2,3,3a,5,6,7,8,11,12,20,21,22,23,24,24a-hexadecahydro-1OH-9,12-methanocyclopenta[18,19][1,10,3,6]dioxadiazacyclononadecino[11,12-b]quinoxaline-10-carboxamide

Example 41 was prepared in a similar fashion to Example 39, substitutingIntermediate A8 for Intermediate A10 in Step 8. Example 41 was isolated(4.3 mg) in approximately 92% purity. Analytic HPLC RetTime: 9.36 min.LCMS-ESI (m/z): [M+H]⁺ calcd for C₄₂H₅₉F₂N₆O₉S: 889.4. found: 889.5. ¹HNMR (300 MHz, CD₃COCD₃) δ 7.83 (d, J=7.83 Hz, 1H), 7.19-7.30 (m, 1H),5.74-6.30 (m, 3H), 4.70 (d, J=7.2 Hz, 1H), 4.19 (dd, J=12.0, 6.0 Hz,1H), 4.24 (d, J=9.6 Hz, 1H), 4.12 (d, J=12.0, 9.6 Hz, 1H), 3.96 (s, 3H),3.10-3.26 (m, 1H), 2.56-2.80 (m, 2H), 2.30-0.80 (m, 25H), 1.54 (s, 3H),1.42 (s, 3H), 1.12 (t, J=7.2 Hz, 3H), 1.06 (s, 9H).

Example 42 and Example 43 Preparation of(1aS,5S,8S,9S,10R,22aS)-5-tert-butyl-N-[(1R,2R)-2-(difluoromethyl)-1-{[(1-methylcyclopropyl)sulfonyl]carbamoyl}cyclopropyl]-1a-ethyl-14-methoxy-9-methyl-3,6-dioxo-1,1a,3,4,5,6,9,10,18,19,20,21,22,22a-tetradecahydro-8H-7,10-methanocyclopropa[18,19][1,10,3,6]dioxadiazacyclononadecino[11,12-b]quinoxaline-8-carboxamideand(1aR,5S,8S,9S,10R,22aR)-5-tert-butyl-N-[(1R,2R)-2-(difluoromethyl)-1-{[(1-methylcyclopropyl)sulfonyl]carbamoyl}cyclopropyl]-1a-ethyl-14-methoxy-9-methyl-3,6-dioxo-1,1a,3,4,5,6,9,10,18,19,20,21,22,22a-tetradecahydro-8H-7,10-methanocyclopropa[18,19][1,10,3,6]dioxadiazacyclononadecino[11,12-b]quinoxaline-8-carboxamide

Step 1. Preparation of 43-1: To a solution of Intermediate mixture D15(281 mg, 0.81 mmol) and Intermediate 18-2 (290 mg, 0.74 mmol) in MeCN(3.7 mL) was added HATU (308 mg, 0.81 mmol) followed by DIPEA (640 μL,3.68 mmol) at rt under an argon atmosphere. After 17 h, the reactionmixture was concentrated in vacuo, and the crude residue was purified bysilica gel chromatography (0-100% ethyl acetate/hexanes) to afford 43-1(121 mg, 1:1 diastereomeric mixture) as a colorless oil. LCMS-ESI (m/z):[M+H]⁺ calcd for C₃₆H₅₂ClN₄O₇: 687.3. found: 687.5.

Step 2. Preparation of 43-2: To a solution of diastereomeric mixture43-1 (121 mg, 176 μmol), TEA (38 μL, 264 μmol) and potassiumvinyltrifluoroborate (35.4 mg, 264 μmol) in EtOH (0.88 mL) was addedPdCl₂(dppf) (14.4 mg, 17.6 μmol). The reaction mixture was degassed withargon for 10 min and heated to 78° C. After 25 min, the reaction mixturewas allowed to cool to rt and was concentrated in vacuo. The cruderesidue was purified by silica gel chromatography (0-100% ethylacetate/hexanes) to afford 43-2 (105 mg, 1:1 diastereomeric mixture) asa yellow oil. LCMS-ESI⁺ (m/z): [M+H]⁺ calcd for C₃₈H₅₅N₄O₇: 679.4.found: 679.5.

Step 3. Preparation of 43-3: To a solution of diastereomeric mixture43-2 (105 mg, 155 μmol) in DCE (31 mL) was added Zhan 1B catalyst (11.3mg, 15.5 μmol, Strem) and the reaction mixture was degassed for 10minutes with argon. The reaction mixture was then heated to 100° C.After 15 min, the reaction mixture was allowed to cool to rt and wasconcentrated in vacuo. The crude residue was purified by silica gelchromatography (0-100% ethyl acetate/hexanes) to afford 43-3 (52.3 mg,1:1 diastereomeric mixture) as a light yellow oil. LCMS-ESI⁺ (m/z):[M+H]⁺ calcd for C₃₆H₅₁N₄O₇: 651.4. found: 651.5.

Step 4. Preparation of 43-4: To a solution of diastereomeric mixture43-3 (52 mg, 80 μmol) in ethanol (0.4 mL) was added Pd/C (10 wt % Pd, 9mg, 8 μmol) at rt under an argon atmosphere. The atmosphere was replacedwith hydrogen and the reaction mixture was stirred vigorously at rt.After 45 min, the reaction mixture was diluted with ethyl acetate (1 mL)and was filtered through a pad of Celite with ethyl acetate washings(3×1 mL). The filtrate was concentrated in vacuo to afford 43-4 (49 mg,1:1 diastereomeric mixture), which was used directly in the next stepwithout further purification. LCMS-ESI (m/z): [M+H]⁺ calcd forC₃₆H₅₂N₄O₇: 653.4. found: 653.6.

Step 5. Preparation of 43-5: To a solution of diastereomeric mixture43-4 (49 mg, 67 μmol) in DCM (0.5 mL) was added TMSOTf (60 μL, 0.34mmol) at rt under an argon atmosphere. After 3 h, the reaction mixturewas added slowly to a 0.25 N aqueous NaOH solution (precooled to 0° C.,1 mL). The resulting mixture was diluted with 1 N aqueous HCl solution(5 mL), and was extracted with DCM (3×5 mL). The combined organicextracts were dried over anhydrous sodium sulfate and were concentratedto afford 43-5 (71 mg, 1:1 diastereomeric mixture) as a tan solid, whichwas used directly in the next step without further purification.LCMS-ESI⁺ (m/z): [M+H]⁺ calcd for C₃₂H₄₅N₄O₇: 597.3. found: 597.5.

Step 6. Preparation of Examples 42 and 43: To a solution ofdiastereomeric mixture 43-5 (71 mg, ˜67 μmol) and Intermediate A10 (54mg, 178 μmol) in MeCN (1.00 mL) was added HATU (69 mg, 178 μmol)followed by DIPEA (155 μL, 0.89 mmol) at rt under an argon atmosphere.After 1 h, the reaction mixture was concentrated in vacuo, and the cruderesidue was purified by silica gel chromatography (0-100% ethylacetate/hexanes). The fractions containing the desired product werecombined and repurified by preparatory HPLC (Gemini 5u C18 110 Å column,50-100% MeCN/H₂O, 0.1% trifluoroacetic acid modifier) and werelyophilized to afford Example 42 (10 mg) and Example 43 (10 mg) as offwhite powders. Example 42: Analytic HPLC RetTime: 9.04 min. [M+H]⁺ calcdfor C₄₁H₅₇F₂N₆O₉S: 847.4. found: 847.6. ¹H NMR (400 MHz, CD₃OD) δ 8.98(s, 1H), 7.73 (d, J=8.4 Hz, 2H), 7.20-7.13 (m, 2H), 5.70 (td, J=55.8,6.4 Hz, 1H), 5.65 (d, J=3.7 Hz, 1H), 5.44 (br s, 1H), 4.55-4.42 (m, 1H),4.20-4.03 (m, 1H), 3.87 (s, 3H), 3.17-3.08 (m, 1H), 2.85-2.72 (m, 1H),2.71-2.59 (m, 1H), 2.18-2.06 (m, 1H), 2.03-1.83 (m, 4H), 1.80-1.53 (m,5H), 1.50 (br s, 3H), 1.46 (s, 3H), 1.40-1.31 (m, 1H), 1.33-1.09 (m,5H), 1.06 (s, 9H), 1.05-0.95 (m, 6H), 0.92-0.73 (m, 3H). Example 43:Analytic HPLC RetTime: 9.17 min. [M+H]⁺ calcd for C₄₁H₅₇F₂N₆O₉S: 847.4.found: 847.6. ¹H NMR (400 MHz, CD₃OD) δ 9.03 (s, 1H), 7.68 (d, J=9.5 Hz,1H), 7.14-7.09 (m, 2H), 5.68 (td, J_(H-F)=55.5, 6.7 Hz, 1H), 5.59 (d,J=3.7 Hz, 1H), 4.45 (d, J=6.8 Hz, 1H), 4.29 (d, J=12.1 Hz, 1H), 4.12 (s,1H), 4.08 (dd, J=12.1, 4.3 Hz, 1H), 3.82 (s, 3H), 2.90-2.79 (m, 1H),2.79-2.70 (m, 1H), 2.66-2.56 (m, 1H), 2.43-2.31 (m, 1H), 1.95-1.85 (m,2H), 1.75-1.62 (m, 1H), 1.61-1.42 (m, 5H), 1.44 (br s, 3H) 1.40 (s, 3H),1.34-1.02 (m, 8H), 1.00 (s, 9H), 0.99-0.89 (m, 5H), 0.85-0.74 (m, 3H).

Example 44 Preparation of(1aR,5S,8S,9S,10R,22aR)-5-tert-butyl-N-[(1R,2R)-2-(difluoromethyl)-1-{[(1-methylcyclopropyl)sulfonyl]carbamoyl}cyclopropyl]-14-methoxy-1a,9-dimethyl-3,6-dioxo-1,1a,3,4,5,6,9,10,18,19,20,21,22,22a-tetradecahydro-8H-7,10-methanocyclopropa[18,19][1,10,3,6]dioxadiazacyclononadecino[11,12-b]quinoxaline-8-carboxamide

Step 1. Preparation of 44-1: HATU (544 mg, 1.43 mmol, Oakwood) and DIPEA(0.83 mL, 4.76 mmol) were added to a mixture of 18-2 (429 mg, 1.09 mmol)and a Intermediate mixture D6 (395 mg, 1.33 mmol) in 12 mL ofacetonitrile under argon. After stirring overnight, the reaction mixturewas concentrated under reduced pressure and the resulting residue waspurified by silica gel chromatography (0-30% ethyl acetate in hexanes)to produce 44-1 (545 mg; 1:1 mixture of diastereomers) as a white solid.LCMS-ESI (m/z): [M+H]⁺ calcd for C₃₅H₅₀ClN₄O₇: 673.33. found: 673.47.

Step 2. Preparation of 44-2: Pd(dppf)Cl₂*CH₂Cl₂ (74 mg, 0.091 mmol,Strem) was added to a deoxygenated mixture of 44-1 (542 mg, 0.805 mmol),potassium vinyltrifluoroborate (168 mg, 1.25 mmol), and triethylamine(0.170 mL, 1.21 mmol) in 9 mL of EtOH at room temperature. Reactionmixture was heated at 78° C. under argon for 75 minutes. After coolingto rt, 6 mL of toluene was added and reaction mixture was concentratedin vacuo. The resulting residue was purified by silica gelchromatography (0-35% ethyl acetate in hexanes) to yield 44-2 (438 mg;1:1 mixture of diastereomers) as a yellow film. LCMS-ESI (m/z): [M+H]⁺calcd for C₃₇H₅₃N₄O₇: 665.38. found: 665.55.

Step 3. Preparation of 44-3 and 44-4: A diastereomeric mixture 44-2 (437mg, 0.658 mmol) and Zhan 1B catalyst (81 mg, 0.072 mmol, Strem) in 131mL of DCE was deoxygenated under argon for 25 minutes. The mixture wasthen heated at 95° C. for 50 minutes. An additional 7 mg of Zhan 1Bcatalyst was added and reaction mixture was heated at 95° C. for 10minutes. After cooling to room temperature, reaction mixture wasconcentrated in vacuo. The resulting residue was purified by silica gelchromatography (0-40% ethyl acetate in hexanes) to yield singlediastereomers 44-3 (143 mg, early eluting component) as a light yellowfilm and 44-4 (118 mg, late eluting component) as a light yellow solid.Early eluting 44-3: LCMS-ESI (m/z): [M+H]⁺ calcd for C₃₅H₄₉N₄O₇: 637.35.found: 637.45. Late eluting 44-4: LCMS-ESI⁺ (m/z): [M+H]⁺ calcd forC₃₅H₄₉N₄O₇: 637.35. found: 637.59.

Step 4. Preparation of 44-5: Palladium on carbon (10 wt % Pd, 48 mg,0.045 mmol) was added to a solution of 44-3 (143 mg, 0.225 mmol) in 6 mLof ethanol. The atmosphere was replaced with hydrogen and the reactionstirred for 90 minutes. The reaction mixture was filtered over Celiteand washed with ethyl acetate. Filtrate was concentrated in vacuo toyield 44-5 (130 mg) as brown solid film, which was used in the next stepwithout further purification. LCMS-ESI⁺ (m/z): [M+H]⁺ calcd forC₃₅H₅₁N₄O₇: 639.37. found: 639.53.

Step 5. Preparation of 44-6: TMSOTf (0.53 mL, 2.91 mmol) was addeddropwise to a solution of 44-5 (130 mg, 1.27 mmol) in 3.8 mL ofdichloromethane under argon at room temperature. After one hour, anadditional 0.22 mL of TMSOTf was added. After an additional hour, 0.20mL of TMSOTf was added. After 40 minutes, 0.25 mL of TMSOTf was added.After one hour, reaction mixture was taken up in 10 mL ofdichloromethane and quenched by addition of 20 mL of 1 N aqueous HClwith stirring. Layers were separated and aqueous was extracted withdichloromethane (3×30 mL). Combined organics were washed with brine,dried over anhydrous Na₂SO₄, filtered, and concentrated in vacuo toyield 44-6 (113 mg) as an off white solid, which was used in the nextstep without further purification. LCMS-ESI (m/z): [M+H]⁺ calcd forC₃₁H₄₃N₄O₇: 583.31. found: 583.45.

Step 6. Preparation of Example 44: HATU (53 mg, 0.139 mmol) and DIPEA(0.080 mL, 0.459 mmol) were added to a mixture of 44-6 (51 mg, 0.088mmol) and Intermediate A10 (49 mg, 0.161 mmol) in 1.5 mL of MeCN underargon. After stirring for overnight, an additional 13 mg of IntermediateA10 was added. After one hour, reaction mixture was taken up in 15 mL ofethyl acetate and poured into 20 mL of 1 N aqueous HCl. Layers wereseparated and aqueous was extracted three times with ethyl acetate.Combined organics were washed with water and brine, dried over anhydrousNa₂SO₄, filtered, and concentrated in vacuo. The resulting residue waspurified by silica gel chromatography (0-40% ethyl acetate in hexanes)to yield Example 44 (41 mg) as an off white solid. Analytic HPLCRetTime: 8.86 min. LCMS-ESI⁺ (m/z): [M+H]⁺ calcd for C₄₀H₅₅F₂N₆O₉S:833.36. found: 833.51. ¹H NMR (400 MHz, CD₃OD): 7.79 (d, J=10 Hz, 1H),7.28-7.21 (m, 2H), 6.77 (d, J=8.4 Hz, 1H), 5.81 (td, J_(H-F)=56 Hz,J=6.4 Hz, 1H), 5.73-5.70 (m, 1H), 4.56 (d, J=7.2 Hz, 1H), 4.40 (d,J=11.6 Hz, 1H), 4.26-4.16 (m, 2H), 3.93 (s, 3H), 3.05-2.91 (m, 1H),2.90-2.82 (m, 1H), 2.77-2.68 (m, 1H), 2.06-1.94 (m, 2H), 1.88-1.74 (m,1H), 1.72-1.58 (m, 3H), 1.58-1.44 (m, 4H), 1.53 (s, 3H), 1.51 (s, 3H),1.43-1.36 (m, 1H), 1.12-1.02 (m, 2H), 1.09 (s, 9H), 1.07 (d, J=4 Hz,3H), 1.00-0.94 (m, 2H), 0.92-0.84 (m, 3H), 0.16-0.11 (m, 1H).

Example 45 Preparation of(1aS,5S,8S,9S,10R,22aS)-5-tert-butyl-N-[(1R,2R)-2-(difluoromethyl)-1-{[(1-methylcyclopropyl)sulfonyl]carbamoyl}cyclopropyl]-14-methoxy-1a,9-dimethyl-3,6-dioxo-1,1a,3,4,5,6,9,10,18,19,20,21,22,22a-tetradecahydro-8H-7,10-methanocyclopropa[18,19][1,10,3,6]dioxadiazacyclononadecino[11,12-b]quinoxaline-8-carboxamide

Example 45 was prepared in a similar fashion to Example 44, substitutinglate eluting 44-4 for early eluting 44-3 in step 4. Example 45 wasisolated (23 mg) as an off white solid. Analytic HPLC RetTime: 8.92 min.LCMS-ESI⁺ (m/z): [M+H]⁺ calcd for C₄₀H₅₅F₂N₆O₉S: 833.36. found: 833.54.¹H NMR (400 MHz, CD₃OD): 7.79 (d, J=9.2 Hz, 1H), 7.25-7.19 (m, 2H), 6.55(d, J=5.2 Hz, 1H), 5.78 (td, J_(H-F)=61 Hz, J=6 Hz, 1H), 5.52-5.48 (m,1H), 4.58 (d, J=6.4 Hz, 1H), 4.52 (d, J=12 Hz, 1H), 4.17-4.10 (m, 1H),4.04 (d, J=6.4 Hz, 1H), 3.93 (s, 3H), 3.22-3.14 (m, 1H), 2.88-2.80 (m,1H), 2.78-2.66 (m, 1H), 2.08-1.90 (m, 2H), 1.76-1.64 (m, 1H), 1.63-1.50(m, 7H), 1.51 (s, 3H), 1.47-1.36 (m, 2H), 1.46 (s, 3H), 1.18-1.06 (m,1H), 1.12 (s, 9H), 1.07 (m, 3H), 1.00-0.80 (m, 4H), 0.10-0.04 (m, 1H).

Example 46 and 47 Preparation of(1aR,5S,8S,9S,10R,22aR)-5-tert-butyl-N-[(1R,2R)-2-(difluoromethyl)-1-{[(1-methylcyclopropyl)sulfonyl]carbamoyl}cyclopropyl]-18,18-difluoro-14-methoxy-9-methyl-3,6-dioxo-1,1a,3,4,5,6,9,10,18,19,20,21,22,22a-tetradecahydro-8H-7,10-methanocyclopropa[18,19][1,10,3,6]dioxadiazacyclononadecino[11,12-b]quinoxaline-8-carboxamideand(1aR,5S,8S,9S,10R,22aR)-5-tert-butyl-N-[(1R,2R)-2-(difluoromethyl)-1-{[(1-methylcyclopropyl)sulfonyl]carbamoyl}cyclopropyl]-18-fluoro-14-methoxy-9-methyl-3,6-dioxo-1,1a,3,4,5,6,9,10,18,19,20,21,22,22a-tetradecahydro-8H-7,10-methanocyclopropa[18,19][1,10,3,6]dioxadiazacyclononadecino[11,12-b]quinoxaline-8-carboxamide

Step 1. Preparation of 46-1: A mixture of Intermediate B1 (627 mg, 2.08mmol), Intermediate E3 (548 mg, 1.91 mmol) and cesium carbonate (744 mg,2.28 mmol) in 7 mL of DMF was stirred at 85° C. under argon for 36hours. Reaction mixture was cooled to room temperature and poured into30 mL of water and aqueous was extracted with ethyl acetate (3×30 mL).Combined organics were washed with water, brine, dried over anhydrousNa₂SO₄, filtered, and concentrated in vacuo. The resulting residue waspurified by silica gel chromatography (0-30% ethyl acetate in hexanes)to yield 46-1 (891 mg) as a white solid. LCMS-ESI (m/z): [M+H]⁺ calcdfor C₂₇H₃₆F₂N₃O₆: 536.25. found: 536.35.

Step 2. Preparation of 46-2: Quinoxaline ether 46-1 (478 mg, 0.893 mmol)was dissolved in 4.2 mL of tert-butyl acetate and 1.1 mL ofdichloromethane at room temperature. MeSO₃H (0.30 mL, 4.67 mmol) wasadded dropwise and reaction mixture stirred at rt for 2 h. The reactionmixture was transferred to a stirred mixture of EtOAc (20 mL) andsaturated aqueous NaHCO₃ (30 mL). The phases were separated, and theaqueous phase was extracted with EtOAc (2×20 mL). The combined organicphase was dried over anhydrous Na₂SO₄, filtered, and concentrated invacuo to afford amine 46-2 as a yellow solid film (346 mg). LCMS-ESI(m/z): [M+H]⁺ calcd for C₂₂H₂₈F₂N₃O₄: 436.20. found: 436.29.

Step 3. Preparation of 46-3: HATU (396 mg, 1.04 mmol, Oakwood) and DIPEA(0.57 mL, 3.29 mmol) were added to a mixture of 46-2 (345 mg, 0.793mmol) and Intermediate D11 (260 mg, 0.965 mmol) in 9 mL of acetonitrileunder argon. After stirring overnight, the reaction mixture wasconcentrated under reduced pressure and the resulting residue waspurified by silica gel chromatography (0-40% ethyl acetate in hexanes)to yield 46-3 (545 mg) as a clear solid film. LCMS-ESI (m/z): [M+H]⁺calcd for C₃₆H₄₉F₂N₄O₇: 687.35. found: 687.57.

Step 4. Preparation of 46-4: A mixture of 46-3 (480 mg, 0.699 mmol) andZhan 1B catalyst (61 mg, 0.083 mmol, Strem) in 140 mL of DCE wasdeoxygenated with argon for 18 minutes. The mixture was then heated at95° C. for 70 minutes. An additional 20 mg of Zhan 1B catalyst was addedand mixture stirred at 95° C. for one hour. After cooling to roomtemperature, reaction mixture was concentrated in vacuo. The resultingresidue was purified by silica gel chromatography (0-35% ethyl acetatein hexanes) to yield an inseparable mixture of 46-4 (major), andapproximately 15% of 47-1 (minor; 233 mg total) as an off white solid.Major component 46-4: LCMS-ESI (m/z): [M+H]⁺ calcd for C₃₄H₄₅F₂N₄O₇:665.38. found: 665.50. Minor component 47-1: LCMS-ESI (m/z): [M+H]⁺calcd for C₃₄H₄₄FN₄O₇: 639.31. found: 639.49.

Step 5. Preparation of mixture of 46-5 and 47-2: Palladium on carbon (10wt % Pd, 70 mg, 0.066 mmol) was added to a solution of the mixture of46-4 and 47-1 (232 mg, 0.353 mmol) from the previous step in 9 mL ofethanol. The atmosphere was replaced with hydrogen and stirred for 7 h.The reaction was filtered over Celite, washing with ethanol. Filtratewas concentrated in vacuo to yield a mixture of 46-5 (major) and 47-2(minor; 216 mg total) as an off white solid, which was used in the nextstep without further purification. Major component 46-5: LCMS-ESI (m/z):[M+H]⁺ calcd for C₃₄H₄₇F₂N₄O₇: 661.33. found: 661.52. Minor component47-2: LCMS-ESI⁺ (m/z): [M+H]⁺ calcd for C₃₄H₄₈FN₄O₇: 643.34. found:643.57.

Step 6. Preparation of mixture of 46-6 and 47-3: TMSOTf (0.35 mL, 1.90mmol) was added dropwise to a solution of a mixture of 46-5 and 47-2(215 mg, 0.326 mmol) from the previous step in 6.5 mL of dichloromethaneunder argon at rt. After 1 h, an additional 0.18 mL of TMSOTf was added.After an additional hour, 0.30 mL of TMSOTf was added. After 2 h, 0.18mL of TMSOTf was added. After 1 h, an additional 0.18 mL of TMSOTf wasadded. After 45 minutes, reaction mixture was taken up in 25 mL ofdichloromethane and quenched by addition of 30 mL of 1 N aqueous HClwith stirring. The aqueous layer was extracted with dichloromethane(3×40 mL). Combined organics were washed with brine, dried overanhydrous Na₂SO₄, filtered, and concentrated in vacuo to yield aninseparable mixture of 46-6 (major) and 47-3 (minor; 187 mg total),which was used in the next step without further purification. Majorcomponent 46-6: LCMS-ESI⁺ (m/z): [M+H]⁺ calcd for C₃₀H₃₉F₂N₄O₇: 605.27.found: 605.44.

Minor component 47-3: LCMS-ESI⁺ (m/z): [M+H]⁺ calcd for C₃₀H₃₉FN₄O₇:587.28. found: 587.38.

Step 7. Preparation of Example 46 and Example 47: HATU (160 mg, 0.421mmol, Oakwood) and DIPEA (0.25 mL, 1.44 mmol) were added to a mixture of46-6 and 47-3 (150 mg, 0.248 mmol) from the previous step andIntermediate A10 (150 mg, 0.496 mmol) in 6.5 mL of acetonitrile underargon. After stirring for overnight, reaction mixture was taken up in 30mL of ethyl acetate and poured into 30 mL of 1 N aqueous HCl. Theaqueous layer was extracted three times with ethyl acetate. Combinedorganics were washed with water and brine, dried over anhydrous Na₂SO₄,filtered, and concentrated in vacuo. The resulting residue was purifiedby silica gel chromatography (0-50% ethyl acetate in hexanes) andreverse phase prep HPLC (50-100% acetonitrile in water, with 0.1%trifluoroacetic acid buffer) to yield the trifluoroacetic acid salt ofExample 46 (107 mg) as a light yellow solid and the trifluoroacetic acidsalt of the 1:1 mixture of diastereomers of Example 47 (12 mg) as alight yellow solid. Example 46: Analytic HPLC RetTime: 8.60 min.LCMS-ESI (m/z): [M+H]⁺ calcd for C₃₉H₅₁F₄N₆O₉S: 855.33. found: 855.63.¹H NMR (400 MHz, CD₃OD): δ 9.23 (s, 1H), 7.94 (d, J=9.2 Hz, 1H), 7.31(dd, J=9.2, 2.8 Hz, 1H), 7.28 (d, J=2.8 Hz, 1H), 5.78 (td, J_(H-F)=66Hz, J=6.8 Hz, 1H), 5.68-5.66 (m, 1H), 4.57 (d, J=6.4 Hz, 1H), 4.41 (d,J=12 Hz, 1H), 4.35 (s, 1H), 4.22-4.16 (dd, J=12, 4 Hz, 1H), 3.97 (s,3H), 3.72-3.66 (m, 1H), 2.86-2.76 (m, 1H), 2.64-2.48 (m, 1H), 2.11-1.94(m, 3H), 1.86-1.74 (m, 3H), 1.73-1.62 (m, 1H), 1.58-1.54 (m, 2H), 1.50(s, 3H), 1.49-1.44 (m, 1H), 1.42-1.38 (m, 1H), 1.11-1.04 (m, 4H), 1.09(s, 9H), 1.02-0.94 (m, 2H), 0.93-0.86 (m, 2H), 0.78-0.66 (m, 1H),0.54-0.46 (m, 1H). Example 47 (1:1 mixture of diastereomers): AnalyticHPLC RetTime: 8.45 min. LCMS-ESI (m/z): [M+H]⁺ calcd for C₃₉H₅₂F₃N₆O₉S:837.34. found: 837.63. ¹H NMR (400 MHz, CD₃OD): δ 9.13 (s, 1H), 7.89 (d,J=8.8 Hz, 1H), 7.27 (dd, J=9.2, 2.8 Hz, 1H), 7.24 (d, J=2.8 Hz, 1H),5.99-5.43 (m, 1H), 5.79 (td, J_(H-F)=55 Hz, J=6.8 Hz, 1H), 5.53-5.50 (m,1H), 4.57-4.44 (m, 2H), 4.11 (s, 1H), 4.35 (s, 1H), 4.22-4.13 (dd,J=12.4, 4 Hz, 1H), 3.95 (s, 3H), 3.83-3.79 (m, 1H), 2.94-2.80 (m, 2H),2.28-2.14 (m, 1H), 2.06-1.96 (m, 2H), 1.88-1.69 (m, 4H), 1.58-1.54 (m,2H), 1.51 (s, 3H), 1.44-1.36 (m, 1H), 1.32-1.26 (m, 1H), 1.14-1.04 (m,4H), 1.10 (s, 9H), 1.02-0.86 (m, 4H), 0.74-0.64 (m, 1H), 0.58-0.48 (m,1H).

Example 48 Preparation of(1aR,5S,8S,9S,10R,22aR)-5-tert-butyl-N-{(1R,2S)-1-[(cyclopropylsulfonyl)carbamoyl]-2-ethenylcyclopropyl}-14-methoxy-9-methyl-3,6-dioxo-1,1a,3,4,5,6,9,10,18,19,20,21,22,22a-tetradecahydro-8H-7,10-methanocyclopropa[18,19][1,10,3,6]dioxadiazacyclononadecino[11,12-b]quinoxaline-8-carboxamide

Step 1: Preparation of Example 48: To a suspension of acid 18-7 (9.7 mg,0.017 mmol) and Intermediate A1 (13 mg, 0.049 mmol) in MeCN (0.4 mL) wasadded DIPEA (40 μL, 0.23 mmol). To the resulting solution was added HATU(12.5 mg, 0.033 mmol). The reaction was stirred at rt for 1 h and wasdiluted with EtOAc (2 mL), 0.2 M aqueous HCl (1 mL), and brine (1 mL).The phases were separated and the aqueous phase was extracted with EtOAc(3×2 mL). The combined organic phase was dried over anhydrous Na₂SO₄,filtered, and concentrated to afford a crude residue that was dissolvedin CH₂Cl₂ and adsorbed onto 1 g silica gel. Purification by silica gelchromatography (10% to 50% acetone in hexanes) provided a residue thatwas lyophilized from water and MeCN to provide Example 48 as a whiteamorphous solid (8.4 mg). Analytic HPLC RetTime: 8.52 min. LCMS-ESI⁺(m/z): [M+H]*calcd for C₃₉H₅₃N₆O₉S: 781.4. found: 781.2. ¹H NMR (400MHz, CDCl₃) δ 9.91 (s, 1H), 7.83 (d, J=9.1 Hz, 1H), 7.19 (dd, J=9.1, 2.7Hz, 1H), 7.10 (d, J=2.7 Hz, 1H), 6.73 (s, 1H), 5.86-5.72 (m, 1H), 5.57(d, J=3.8 Hz, 1H), 5.48 (d, J=9.9 Hz, 1H), 5.27-5.15 (m, 1H), 5.15-5.07(m, 1H), 4.48-4.35 (m, 3H), 4.12 (dd, J=11.8, 4.1 Hz, 1H), 3.94 (s, 3H),3.81-3.71 (m, 1H), 2.98-2.75 (m, 4H), 2.16-2.09 (m, 1H), 1.94 (dd,J=8.2, 5.8 Hz, 1H), 1.87-1.24 (m, 9H), 1.17 (d, J=7.4 Hz, 3H), 1.09 (s,9H), 1.04-0.91 (m, 5H), 0.75-0.65 (m, 1H), 0.52-0.42 (m, J=6.0 Hz, 1H).

Example 49 Preparation of(1aS,2aR,6S,9S,10S,11R,23aR,23bS)-6-tert-butyl-N-[(1R,2R)-2-(difluoromethyl)-1-{[(1-methylcyclopropyl)sulfonyl]carbamoyl}cyclopropyl]-15-methoxy-10-methyl-4,7-dioxo-1a,2,2a,4,5,6,7,10,11,19,20,21,22,23,23a,23b-hexadecahydro-1H,9H-8,11-methanocyclopropa[4′,5′]cyclopenta[1′,2′:18,19][1,10,3,6]dioxadiazacyclononadecino[11,12-b]quinoxaline-9-carboxamide

Step 1: Preparation of Example 49: To a suspension of acid 33-4 (30 mg,0.049 mmol) and Intermediate A10 (31 mg, 0.10 mmol) in MeCN (700 μL) wasadded DIPEA (70 μL, 0.40 mmol). HATU (32 mg, 0.084 mmol) was added tothe resulting solution, and the reaction was stirred at rt for 1.5 h. Anadditional portion of Intermediate A10 (6 mg, 0.02 mmol) was then added.The reaction was stirred an additional 30 min and was then diluted withEtOAc (30 mL), 0.2 M aqueous HCl (15 mL) and brine (15 mL). The phaseswere separated and the aqueous phase was extracted with EtOAc (30 mL).The combined organic phase was dried over anhydrous Na₂SO₄, filtered,and concentrated to afford a crude residue. This residue was dissolvedin CH₂Cl₂ and adsorbed onto 2 g silica gel. Purification by silica gelchromatography (10% to 50% acetone in hexanes) provided an amorphousresidue that was lyophilized from water and MeCN to provide Example 49as a white amorphous solid (30.5 mg). Analytic HPLC RetTime: 9.15 min.LCMS-ESI (m/z): [M+H]⁺ calcd for C₄₂H₅₇F₂N₆O₉S: 859.4. found: 859.2. ¹HNMR (400 MHz, CDCl₃) δ 9.86 (s, 1H), 7.82 (d, J=9.1 Hz, 1H), 7.45 (s,1H), 7.18 (dd, J=9.1, 2.7 Hz, 1H), 7.08 (d, J=2.7 Hz, 1H), 6.14-5.71 (m,1H), 5.61 (d, J=3.7 Hz, 1H), 5.28 (d, J=9.8 Hz, 1H), 5.00 (d, J=7.4 Hz,1H), 4.49 (d, J=7.0 Hz, 1H), 4.42-4.31 (m, 2H), 4.12 (dd, J=11.6, 4.0Hz, 1H), 3.93 (s, 3H), 3.00-2.63 (m, 4H), 2.25-2.16 (m, 1H), 2.09-1.90(m, 4H), 1.81-0.95 (m, 26H), 0.92-0.75 (m, 3H), 0.57-0.45 (m, 1H),0.44-0.36 (m, 1H).

Example 50 Preparation of(1aR,5S,8S,9S,10R,22aR)-5-tert-butyl-9-(cyanomethyl)-N-[(1R,2R)-2-(difluoromethyl)-1-{[(1-methylcyclopropyl)sulfonyl]carbamoyl}cyclopropyl]-14-methoxy-3,6-dioxo-1,1a,3,4,5,6,9,10,18,19,20,21,22,22a-tetradecahydro-8H-7,10-methanocyclopropa[18,19][1,10,3,6]dioxadiazacyclononadecino[11,12-b]quinoxaline-8-carboxamide

Example 50 was prepared in a similar fashion to Example 1, substitutingIntermediate B8 for Intermediate B4 in step 1. Example 50 was purifiedby reverse phase HPLC (Gemini column, 58-98% ACN/H₂O+0.1% TFA) andlyophilized to afford solid (5 mg) as a TFA salt. Analytic HPLC RetTime:8.29 min. LCMS-ESI⁺ (m/z): [M+H]⁺ calcd for C₄₀H₅₁F₂N₇O₉S: 844.94.found: 844.58. ¹H NMR (400 MHz, CD₃OD) δ 9.71 (s, 1H), 7.79 (d, J=8.8Hz, 1H), 7.22 (m, 2H), 6.25 (m, 1H), 6.08-5.80 (m, 1H), 4.39 (m, 1H),4.29 (m, 2H), 4.13 (m, 1H), 3.92 (s, 3H), 3.65 (m, 1H), 3.06-2.83 (m,4H), 2.55 (m, 1H), 2.14-1.47 (m, 17H), 1.03 (s, 9H), 0.92 (m, 4H), 0.65(m, 1H), 0.45-0.43 (m, 1H).

Example 51 Preparation of(3aR,7S,10S,11S,12R,24aR)-7-tert-butyl-N-{(1R,2R)-1-[(cyclopropylsulfonyl)carbamoyl]-2-ethylcyclopropyl}-1-ethyl-16-methoxy-3a-methyl-5,8-dioxo-1,2,3,3a,5,6,7,8,11,12,20,21,22,23,24,24a-hexadecahydro-1OH-9,12-methanocyclopenta[18,19][1,10,3,6]dioxadiazacyclononadecino[11,12-b]quinoxaline-10-carboxamide

Example 51 was prepared in a similar fashion to Example 39, substitutingIntermediate A3 for Intermediate A10 in step 8. Example 51 was isolated(12.3 mg) in approximately 96.5% purity. Analytic HPLC RetTime: 9.38min. LCMS-ESI⁺ (m/z): [M+H]⁺ calcd for C₄₃H₆₃N₆O₉S: 839.4. found: 839.5.¹H NMR (300 MHz, CD₃OD) δ 7.60 (d, J=8.4 Hz, 1H), 6.98-7.08 (m, 2H),6.53 (d, J=9.6 Hz, 1H), 5.57-5.83 (m, 2H), 4.52 (d, J=8.4 Hz, 2H), 4.24(dd, J=10.8, 6.0 Hz, 1H), 4.02 (d, J=9.6 Hz, 1H), 3.82 (dd, J=10.8, 2.4Hz, 1H), 3.73 (s, 3H), 2.93-3.10 (m, 1H), 2.80-2.90 (m, 2H), 2.30-2.58(m, 2H), 0.60-2.10 (m, 32H), 0.84 (s, 9H).

Example 52 Preparation of(3aR,7S,10S,11S,12R,24aR)-7-tert-butyl-11-ethyl-N-[(1R,2S)-2-(2-fluoroethyl)-1-{[(1-methylcyclopropyl)sulfonyl]carbamoyl}cyclopropyl]-16-methoxy-3a-methyl-5,8-dioxo-1,2,3,3a,5,6,7,8,11,12,20,21,22,23,24,24a-hexadecahydro-10H-9,12-methanocyclopenta[18,19][1,10,3,6]dioxadiazacyclononadecino[11,12-b]quinoxaline-10-carboxamide

Example 52 was prepared in a similar fashion to Example 39, substitutingIntermediate A6 for Intermediate A10 in step 8. Example 52 was isolated(12.3 mg) in approximately 96.5% purity. Analytic HPLC RetTime: 8.60min. Analytic HPLC RetTime: 9.31 min. LCMS-ESI (m/z): [M+H]⁺ calcd forC₄₄H₆₄FN₆O₉S: 871.4. found: 871.5. ¹H NMR (300 MHz, CD₃OD) δ 7.81 (d,J=8.4 Hz, 1H), 7.20-7.30 (m, 2H), 6.73 (d, J=9.6 Hz, 1H), 5.75-6.02 (m,2H), 4.74 (d, J=8.4 Hz, 2H), 4.54 (t, J=6.0 Hz, 2H), 4.36-4.49 (m, 1H),4.23 (d, J=9.6 Hz, 1H), 4.04 (dd, J=12.0, 2.4 Hz, 1H), 3.75 (s, 3H),3.28-3.16 (m, 1H), 2.50-2.70 (m, 2H), 2.30-0.80 (m, 35H), 1.04 (s, 9H).

Example 53 Preparation of(1aR,5S,8S,9S,10R,22aR)-5-tert-butyl-N-[(1R,2R)-1-[(cyclopropylsulfonyl)carbamoyl]-2-(difluoromethyl)cyclopropyl]-9-ethyl-18,18-difluoro-3,6-dioxo-1,1a,3,4,5,6,9,10,18,19,20,21,22,22a-tetradecahydro-8H-7,10-methanocyclopropa[18,19][1,10,3,6]dioxadiazacyclononadecino[11,12-b]quinoxaline-8-carboxamide

Example 53 was prepared similarly to Example 17 substitutingIntermediate E4 for Intermediate E3 in Step 1 and Intermediate A9 forIntermediate A10 in Step 7. Example 53 was isolated (8.8 mg) as a whitesolid. LCMS-ESI (m/z): [M+H]⁺ calcd for C₃₈H₄₈F₄N₆O₈S: 825.32. found:825.75. ¹H NMR (400 MHz, CDCl₃) δ 10.13 (s, 1H), 8.15 (d, J=8.2 Hz, 1H),7.91-7.74 (m, 2H), 7.69 (t, J=7.6 Hz, 1H), 6.92 (s, 1H), 5.47 (d, J=9.6Hz, 1H), 4.48 (t, J=10.3 Hz, 2H), 4.36 (d, J=9.4 Hz, 1H), 4.12 (dd,J=12.1, 3.6 Hz, 1H), 3.70-3.59 (m, 1H), 3.08-2.75 (m, 1H), 2.58-2.38 (m,1H), 2.14 (t, J=6.8 Hz, 1H), 1.95-1.67 (m, 4H), 1.47 (tt, J=13.9, 7.1Hz, 4H), 1.35 (s, 2H), 1.20 (t, J=7.3 Hz, 3H), 1.15-0.64 (m, 19H), 0.51(q, J=6.4 Hz, 1H).

Example 54 Preparation of(1aR,5S,8S,9S,10R,22aR)-5-tert-butyl-N-{(1R,2R)-1-[(cyclopropylsulfonyl)carbamoyl]-2-ethylcyclopropyl}-9-ethyl-18,18-difluoro-3,6-dioxo-1,1a,3,4,5,6,9,10,18,19,20,21,22,22a-tetradecahydro-8H-7,10-methanocyclopropa[18,19][1,10,3,6]dioxadiazacyclononadecino[11,12-b]quinoxaline-8-carboxamide

Example 54 was prepared similarly to Example 53 replacing IntermediateA9 with Intermediate A3. Example 54 was isolated (10.0 mg) as a whitesolid. LCMS-ESI (m/z): [M+H]⁺ calcd for C₃₉H₅₂F₂N₆O₈S: 803.35. found:803.79. ¹H NMR (400 MHz, CDCl₃) δ 9.88 (s, 1H), 8.12 (d, J=8.2 Hz, 1H),7.88-7.69 (m, 2H), 7.66 (t, J=7.6 Hz, 1H), 6.68 (s, 1H), 5.95 (d, J=3.4Hz, 1H), 5.46 (d, J=9.4 Hz, 1H), 4.45 (dd, J=13.8, 9.7 Hz, 2H), 4.09(dd, J=12.0, 3.6 Hz, 2H), 3.71-3.57 (m, 1H), 2.53 (dd, J=21.4, 14.6 Hz,1H), 1.85-1.39 (m, 10H), 1.38-0.96 (m, 20H), 1.01 (dd, J=17.2, 9.5 Hz,3H), 1.04-0.78 (m, 6H), 0.70 (s, 1H), 0.49 (dd, J=12.7, 6.3 Hz, 1H).

Example 55 Preparation of(1aR,5S,8S,9S,10R,22aR)-5-tert-butyl-N-[(1R,2R)-2-(difluoromethyl)-1-{[(1-methylcyclopropyl)sulfonyl]carbamoyl}cyclopropyl]-9-ethyl-3,6-dioxo-14-(2,2,2-trifluoroethoxy)-1,1a,3,4,5,6,9,10,18,19,20,21,22,22a-tetradecahydro-8H-7,10-methanocyclopropa[18,19][1,10,3,6]dioxadiazacyclononadecino[11,12-b]quinoxaline-8-carboxamide

Intermediate 55-1 was prepared by following Steps 1 through 6 of Example1, substituting for Intermediate E2 for Intermediate E1 in Step 1.LCMS-ESI⁺ (m/z): [M+H]⁺ calcd for C₃₄H₄₉N₄O₇: 625.36. found: 625.25.

Step 1. Preparation of 55-2. Quinoxalinol 55-1 (24 mg, 0.038 mmol) wassuspended in DMF (2 mL) and treated with Cs₂CO₃ (63 mg, 0.19 mmol) and2,2,2-trifluoroethyl trifluoromethanesulfonate (0.055 mL, 0.38 mmol).The reaction mixture was stirred at RT for 5 h, then diluted with EtOAc.The organic layer was washed with H₂O and brine, dried over MgSO₄,filtered and concentrated under reduced pressure to afford 55-2, whichwas carried on without further purification. LCMS-ESI⁺ (m/z): [M+H]⁺calcd for C₃₆H₅₀F₃N₄O₇: 707.36. found: 707.38.

Step 2. Preparation of 55-3. Trifluoroethyl ether 55-2 (0.038 mmoltheoretical) was treated with DCM (4 mL) and TMSOTf (0.14 mL, 0.77 mmol)at RT. After 1 h, the reaction was quenched by addition of 1M NaOH (2mL). After stirring vigorously for 5 min, the mixture was poured into aseparatory funnel followed by 10% HCl (20 mL). The aqueous layer wasextracted 3× with DCM. The combined organics were dried over MgSO₄,filtered and concentrated under reduced pressure to afford 55-3, whichwas carried on without further purification. LCMS-ESI⁺ (m/z): [M+H]⁺calcd for C₃₂H₄₂F₃N₄O₇: 651.30. found: 651.18.

Step 3. Preparation of Example 55. Carboxcylic acid 55-3 (0.038 mmoltheoretical) was treated with intermediate A10 (23 mg, 0.077 mmol), TBTU(25 mg, 0.077 mmol), DMAP (9 mg, 0.077 mmol), DCM (1 mL) and DIPEA(0.134 mL, 0.768 mmol). The reaction mixture was stirred at RT for 20 h,then concentrated under reduced pressure and purified by reverse phaseHPLC to afford Example 55 as a TFA salt (7 mg, 18% over 3 steps).LCMS-ESI (m/z): [M+H]⁺ calcd for C₄₁H₅₄F₅N₆O₉S: 901.36. found: 902.08.¹H NMR (400 MHz, CD₃OD) δ 9.18 (s, 1H), 7.86 (d, J=9.1 Hz, 1H), 7.32(dd, J=9.1, 2.8 Hz, 1H), 7.25 (d, J=2.7 Hz, 1H), 6.02-5.63 (m, 2H),4.76-4.62 (m, 2H), 4.56 (d, J=7.1 Hz, 1H), 4.39 (t, J=6.0 Hz, 2H), 4.15(dt, J=17.2, 8.6 Hz, 1H), 3.74 (dd, J=6.7, 2.8 Hz, 1H), 3.05-2.89 (m,1H), 2.82 (td, J=13.2, 4.2 Hz, 1H), 2.65-2.50 (m, 1H), 2.02 (d, J=10.4Hz, 2H), 1.78 (dt, J=23.5, 10.7 Hz, 3H), 1.68-1.26 (m, 14H), 1.22 (t,J=7.3 Hz, 3H), 1.10 (s, 9H), 0.97 (d, J=2.5 Hz, 2H), 0.95-0.84 (m, 2H),0.71 (s, 1H), 0.51 (t, J=9.8 Hz, 1H).

Example 56 Preparation of(3aR,7S,10S,11S,12R,24aR)-7-tert-butyl-11-ethyl-N-[(1R,2R)-2-ethyl-1-{[(1-methylcyclopropyl)sulfonyl]carbamoyl}cyclopropyl]-16-methoxy-3a-methyl-5,8-dioxo-1,2,3,3a,5,6,7,8,11,12,20,21,22,23,24,24a-hexadecahydro-10H-9,12-methanocyclopenta[18,19][1,10,3,6]dioxadiazacyclononadecino[11,12-b]quinoxaline-10-carboxamide

Example 56 was prepared in a similar fashion to Example 39, substitutingIntermediate A9 for Intermediate A3 in Step 8. Example 56 was isolated(8.8 mg, 0.0103 mmol, 53.7%). Analytic HPLC RetTime: 9.56 min. LCMS-ESI(m/z): [M+H]⁺ calcd for C₄₄H₆₅N₆O₉S: 853.45. found: 853.5. ¹H NMR (300MHz, CD₃OD) δ 7.81 (d, J=9.6 Hz, 1H), 7.20-7.30 (m, 2H), 6.73 (d, J=9.6Hz, 1H), 5.76-6.01 (m, 2H), 4.75 (d, J=8.4 Hz, 1H), 4.46 (dd, J=12.0,6.0 Hz, 1H), 4.23 (d, J=9.6 Hz, 1H), 4.00-4.08 (m, 1H), 3.95 (s, 3H),2.50-2.78 (m, 3H), 0.80-2.30 (m, 30H), 1.54 (s, 3H), 1.35 (s, 3H), 1.05(s, 9H).

Example 57 Preparation of(1aS,2aR,6S,9S,10S,11R,23aR,23bS)-6-tert-butyl-N-[(1R,2S)-1-[(cyclopropylsulfonyl)carbamoyl]-2-(2,2-difluoroethyl)cyclopropyl]-15-methoxy-10-methyl-4,7-dioxo-1a,2,2a,4,5,6,7,10,11,19,20,21,22,23,23a,23b-hexadecahydro-1H,9H-8,11-methanocyclopropa[4′,5′]cyclopenta[1′,2′:18,19][1,10,3,6]dioxadiazacyclononadecino[11,12-b]quinoxaline-9-carboxamide

Step 1. Preparation of Example 57. To a suspension of acid 33-4 (14.9mg, 0.0245 mmol) and amine hydrochloride A-7 (16.3 mg, 0.0535 mmol) inMeCN (500 μL) was added DIPEA (40 μL, 0.23 mmol). HATU (15.5 mg, 0.0408mmol) was added to the resulting solution, and the reaction was stirredat rt for 17 h. The reaction was then diluted with EtOAc (2 mL), 0.2 Maqueous HCl (1.5 mL) and brine (1.5 mL). The phases were separated andthe aqueous phase was extracted with EtOAc (4×1.5 mL). The combinedorganic phase was dried over Na₂SO₄, filtered, and concentrated toafford a crude residue. This residue was dissolved in CH₂Cl₂ and wasconcentrated onto 1.5 g silica gel. Purification by silica gelchromatography (10% to 40% acetone in hexanes) provided an amorphousresidue that was lyophilized from water and MeCN to provide Example 57.LCMS-ESI⁺ (m/z): [M+H]⁺ calcd for C₄₂H₅₇F₂N₆O₉S: 859.4. found: 859.0. ¹HNMR (300 MHz, CDCl₃) δ 10.00 (s, 1H), 7.82 (d, J=9.1 Hz, 1H), 7.19 (dd,J=9.1, 2.7 Hz, 1H), 7.09 (d, J=2.6 Hz, 1H), 6.75 (s, 1H), 6.07-5.57 (m,2H), 5.26 (d, J=9.8 Hz, 1H), 5.01 (d, J=7.4 Hz, 1H), 4.50-4.29 (m, 3H),4.12 (dd, J=11.7, 3.9 Hz, 1H), 3.93 (s, 3H), 3.00-2.62 (m, 4H),2.34-0.96 (m, 33H), 0.95-0.78 (m, 1H), 0.51 (dd, J=13.0, 7.9 Hz, 1H),0.39 (d, J=4.2 Hz, 1H).

Example 58 Preparation of(1aS,2aR,6S,9S,10S,11R,23aR,23bS)-6-tert-butyl-N-[(1R,2S)-2-(2,2-difluoroethyl)-1-{[(1-methylcyclopropyl)sulfonyl]carbamoyl}cyclopropyl]-15-methoxy-10-methyl-4,7-dioxo-1a,2,2a,4,5,6,7,10,11,19,20,21,22,23,23a,23b-hexadecahydro-1H,9H-8,11-methanocyclopropa[4′,5′]cyclopenta[1′,2′:18,19][1,10,3,6]dioxadiazacyclononadecino[11,12-b]quinoxaline-9-carboxamide

Step 1. Preparation of Example 58. To a suspension of acid 33-4 (14.5mg, 0.0238 mmol) and amine hydrochloride A-8 (16.0 mg, 0.0502 mmol) inMeCN (500 μL) was added DIPEA (40 μL, 0.23 mmol). HATU (15.5 mg, 0.0408mmol) was added to the resulting solution, and the reaction was stirredat rt for 17 h. The reaction was then diluted with EtOAc (2 mL), 0.2 Maqueous HCl (1.5 mL) and brine (1.5 mL). The phases were separated andthe aqueous phase was extracted with EtOAc (4×1.5 mL). The combinedorganic phase was dried over Na₂SO₄, filtered, and concentrated toafford a crude residue. This residue was dissolved in CH₂Cl₂ and wasconcentrated onto 1.5 g silica gel. Purification by silica gelchromatography (10% to 40% acetone in hexanes) provided an amorphousresidue that was lyophilized from water and MeCN to provide Example 58.LCMS-ESI (m/z): [M+H]⁺ calcd for C₄₃H₅₉F₂N₆O₉S: 873.4. found: 873.3. ¹HNMR (300 MHz, CDCl₃) δ 9.72 (s, 1H), 7.82 (d, J=9.1 Hz, 1H), 7.19 (dd,J=9.1, 2.7 Hz, 1H), 7.09 (d, J=2.7 Hz, 1H), 6.82 (s, 1H), 6.12-5.54 (m,2H), 5.25 (d, J=9.8 Hz, 1H), 5.01 (d, J=7.2 Hz, 1H), 4.50-4.30 (m, 3H),4.13 (dd, J=11.7, 4.2 Hz, 1H), 3.93 (s, 3H), 3.03-2.65 (m, 4H),2.34-0.97 (m, 33H), 0.94-0.76 (m, 3H), 0.60-0.45 (m, 1H), 0.45-0.34 (m,1H).

Example 59 Preparation of(1aS,2aR,6S,9S,10S,11R,23aR,23bS)-6-tert-butyl-N-[(1R,2R)-1-[(cyclopropylsulfonyl)carbamoyl]-2-(difluoromethyl)cyclopropyl]-10-ethyl-19,19-difluoro-15-methoxy-4,7-dioxo-1a,2,2a,4,5,6,7,10,11,19,20,21,22,23,23a,23b-hexadecahydro-1H,9H-8,11-methanocyclopropa[4′,5′]cyclopenta[1′,2′:18,19][1,10,3,6]dioxadiazacyclononadecino[11,12-b]quinoxaline-9-carboxamide

Step 1. Preparation of 59-1. A solution of Intermediate D16 (0.50 g, 1.6mmol) in DMF (7 mL) was treated subsequently with COMU (0.80 g, 1.9mmol), DIPEA (1.2 mL, 6.7 mmol) and Intermediate 17-2 (0.65 g, 1.3 mmol)and stirred overnight at rt. The reaction was quenched with 1 M citricacid solution (5 mL) and extracted with EA. The combined organics werewashed with brine, dried over anhydrous MgSO₄ and concentrated in vacuo.The resulting residue was purified by silica gel chromatography (15-100%EA/hex) to afford 59-1. LCMS-ESI⁺ (m/z): [M+H]⁺ calcd for C₄₀H₅₅F₂N₄O₇:741.88. found: 741.51.

Step 2. Preparation of 59-2. A solution of 59-1 (0.51 g, 0.69 mmol) inDCE (140 mL) is sparged with argon for 30 min prior to addition of Zhan1B catalyst (0.051 g, 0.07 mmol). The reaction was heated to 85° C. for45 min, and another portion of Zhan 1B catalyst was added. After anadditional 30 min, the reaction was cooled to rt, concentrated in vacuoand purified by silica gel chromatography (5-100% EA/hex) to produce59-2. LCMS-ESI (m/z): [M+H]⁺ calcd for C₃₈H₅₁F₂N₄O₇: 713.83. found:713.54.

Step 3. Preparation of 59-3. A solution of 59-2 was taken up in EtOH (8mL). Pd/C (0.072 g, 10% w/w) was added and the atmosphere replaced withH₂. After 1 h, additional catalyst was added. After 4 h, EA andadditional catalyst was added. After an additional 3 h, the reaction wasfiltered, concentrated in vacuo, and the residue taken up in EtOH (8 mL)and treated with 0.5 g Pd/C (10% w/w) and the atmosphere replaced withH₂. The reaction was stirred overnight, and then worked up again aspreviously described to produce of 59-3 that was used subsequentlywithout further purification. LCMS-ESI (m/z): [M+H]⁺ calcd forC₃₈H₅₃F₂N₄O₇: 715.85. found: 715.52.

Step 4. Preparation of 59-4. A solution of 59-3 (0.40 g, 0.56 mmol) inDCM (1.5 mL) was treated with 2.5 mL TFA at rt. After 1.5 h, thereaction was concentrated in vacuo. The residue was taken up in EA,washed with saturated aqueous NaHCO₃, brine and then dried overanhydrous MgSO₄. Concentration in vacuo produced 59-4 that was usedsubsequently without further purification. LCMS-ESI (m/z): [M+H]⁺ calcdfor C₃₄H₄₅F₂N₄O₇: 659.74. found: 659.56.

Step 5. Preparation of Example 59: A solution of 59-4 (0.20 g, 0.30mmol) in DMF (2 mL) was treated subsequently with HATU (0.21 g, 0.55mmol), DIPEA (0.27 mL, 1.5 mmol), DMAP (0.056 g, 0.46 mmol), andIntermediate A9 (0.13 g, 0.46 mmol) and stirred for 5 h at rt. Thereaction mixture is purified by preparatory HPLC to produce the TFA saltof Example 59. Analytic HPLC RetTime: 9.20 min. LCMS-ESI (m/z): [M+H]⁺calcd for C₄₂H₅₅F₄N₆O₉S: 895.98. found: 895.60. ¹H NMR (400 MHz, CD₃OD)δ 9.31 (s, 1H); 7.94 (d, J=9.2 Hz, 1H); 7.32 (dd, J=9.2, 2.4 Hz, 1H);7.21 (d, J=2.4 Hz, 1H); 5.98 (br s, 1H); 5.85 (td, J_(H-F)=55.2 Hz, J=6Hz, 1H); 4.94 (d, J=7.6 Hz, 1H); 4.58 (d, J=7.2 Hz, 1H); 4.35 (d, J=7.2Hz, 1H); 4.33 (br s, 1H); 4.18 (dd, J=12, 3.6 Hz, 1H); 3.97 (brs, 3H);2.98 (m, 1H); 2.64-2.41 (m, 2H); 2.22 (m, 1H); 2.15-1.92 (m, 4H);1.84-1.22 (m, 14H); 1.18 (t, J=7.2 Hz, 3H); 1.14-0.98 (m, 2H); 1.08 (s,9H); 0.60-0.48 (m, 2H).

Example 60 Preparation of(1aR,5S,8S,9S,10R,22aR)-5-tert-butyl-N-[(1R,2R)-1-[(cyclopropylsulfonyl)carbamoyl]-2-(difluoromethyl)cyclopropyl]-18,18-difluoro-14-methoxy-3,6-dioxo-9-propyl-1,1a,3,4,5,6,9,10,18,19,20,21,22,22a-tetradecahydro-8H-7,10-methanocyclopropa[18,19][1,10,3,6]dioxadiazacyclononadecino[11,12-b]quinoxaline-8-carboxamide

Step 1. Preparation of 60-1: To a solution of Intermediate B5 (160 mg,0.590 mmol) and Intermediate E3 (194 mg, 0.590 mmol) in MeCN (2.95 mL)was added cesium carbonate (192 mg, 0.590 mmol) at rt under an argonatmosphere. After 24 h, the reaction mixture was then filtered through apad of Celite and the filtrate concentrated in vacuo. The crude residuewas purified by silica gel chromatography (0-100% ethyl acetate/hexanesgradient) to afford substituted quinoxaline 60-1. LCMS-ESI⁺ (m/z):[M+H]⁺ calcd for C₂₉H₄₀F₂N₃O₆: 564.28. found: 564.44.

Step 2. Preparation of 60-2: To a solution 60-1 (193 mg, 0.343 mmol) intert-butyl acetate (1.36 mL) was added a solution of methanesulfonicacid (111 μL, 1.72 mmol) in dichloromethane (0.34 mL) and the reactionwas stirred at rt. After 2 h, the reaction mixture was diluted withsaturated sodium bicarbonate solution (20 mL) and the resulting mixturewas extracted with ethyl acetate (2×20 mL). The combine organics weredried over anhydrous sodium sulfate and were concentrated in vacuo toafford amine hydrochloride 60-2, which was used directly in the nextstep without further purification. LCMS-ESI (m/z): [M+H]⁺ calcd forC₂₄H₃₂F₂N₃O₄: 464.23. found: 464.35.

Step 3. Preparation of 60-3: To a solution of 60-2 (133 mg, 0.289 mmol)and Intermediate D11 (133 mg, 0.412 mmol) in MeCN (1.7 mL) was addedHATU (157 mg, 0.412 mmol) followed by DIPEA (298 μL, 1.72 mmol) at rtunder and argon atmosphere. After 1 h, the reaction mixture wasconcentrated in vacuo, and the crude residue was purified by silica gelchromatography (0-100% ethyl acetate/hexanes gradient) to afford amide60-3. LCMS-ESI (m/z): [M+H]⁺ calcd for C₃₈H₅₃F₂N₄O₇: 715.38. found:715.55.

Step 4. Preparation of 60-4: To a solution of 60-3 (188 mg, 264 μmol) inDCE (52.8 mL) was added Zhan 1B catalyst (19.4 mg, 26.4 μmol) and thereaction mixture was degassed for 10 minutes with argon. The reactionmixture was then heated to 100° C. After 1 h, the reaction mixture wasallowed to cool to rt and was concentrated in vacuo. The crude residuewas purified by silica gel chromatography (0-100% ethyl acetate/hexanesgradient) to afford macrocycle 60-4. LCMS-ESI (m/z): [M+H]⁺ calcd forC₃₆H₄₉F₂N₄O₇: 687.35. found: 687.54.

Step 5. Preparation of 60-5: To a solution of macrocycle 60-4 (119 mg,173 μmol) in ethanol (1.0 mL) was added Pd/C (10 wt %, 18.4 mg, 17.3μmol) at rt under an argon atmosphere. The reaction vessel was evacuatedand refilled with 1 atm hydrogen gas (3×) and the reaction mixture wasstirred vigorously at rt. After 1 h, the reaction mixture was filteredthrough a pad of Celite with ethyl acetate washings (3×2 mL). Thefiltrate was concentrated in vacuo to afford macrocycle 60-5, which wasused directly in the next step without further purification. LCMS-ESI(m/z): [M+H]⁺ calcd for C₃₆H₅₁F₂N₄O₇: 689.36. found: 689.56.

Step 6. Preparation of 60-6: To a solution of 60-5 (150 mg, 218 μmol) inDCM (1.1 mL) was added TMSOTf (197 μL, 1.09 mmol) at rt under an argonatmosphere. After 2 h, the reaction mixture was transferred to asolution of 0.5N NaOH solution (5 mL) precooled to 0° C. The resultingmixture was acidified with 1N HCl solution to pH=2 and was extractedwith dichloromethane (3×5 mL). The combined organic extracts were driedover anhydrous sodium sulfate and were concentrated in vacuo to affordcarboxylic acid 60-6, which was used directly in the next step withoutfurther purification. LCMS-ESI (m/z): [M+H]⁺ calcd for C₃₂H₄₃F₂N₄O₇:633.30. found: 633.49.

Step 7. Preparation of Example 60: To a solution of 60-6 (100 mg, 158μmol) and Intermediate A9 (69.0 mg, 237 μmol) in MeCN (790 μL) was addedHATU (91.5 mg, 237 μmol) followed by DIPEA (137 μL, 790 μmol) at rtunder an argon atmosphere. After 3 h, the reaction mixture wasconcentrated in vacuo, was purified by preparatory HPLC (Gemini 5u C18110 Å column, 5-100% MeCN/H₂O, 0.1% trifluoroacetic acid modifier) andwas lyophilized to afford Example 60 as a TFA salt. Analytic HPLCRetTime: 8.89 min. LCMS-ESI (m/z): [M+H]⁺ calcd for C₄₀H₅₃F₄N₆O₉S:869.35. found: 859.66. ¹H NMR (400 MHz, CD₃OD) δ 9.29 (br s, 1H), 7.94(d, J=9.2 Hz, 1H), 7.31 (d, J=9.2 Hz, 1H), 7.19 (br s, 1H), 5.87 (br s,1H), 5.84 (td, J_(H-F)=55.8 Hz, J=5.4 Hz, 1H), 4.56 (d, J=6.9 Hz, 1H),4.40 (d, J=12.6 Hz, 1H), 4.36 (s, 1H), 4.17 (dd, J=11.9, 3.4 Hz, 1H),3.96 (br s, 4H), 3.68 (br s, 1H), 3.01-2.91 (m, 1H), 2.71-2.61 (m, 1H),2.61-2.43 (m, 1H), 2.02 (br s, 4H), 1.88-1.59 (m, 4H), 1.59-1.35 (m,4H), 1.33-1.20 (m, 3H), 1.09 (s, 9H), 1.04-0.95 (app t, J=7.0 Hz, 5H),0.79-0.65 (m, 1H), 0.49 (d, J=6.5 Hz, 1H).

Example 61 Preparation of(1aS,2aR,6S,9S,10S,11R,23aR,23bS)-6-tert-butyl-N-[(1R,2R)-2-(difluoromethyl)-1-{[(1-methylcyclopropyl)sulfonyl]carbamoyl}cyclopropyl]-10-ethyl-19,19-difluoro-15-methoxy-4,7-dioxo-1a,2,2a,4,5,6,7,10,11,19,20,21,22,23,23a,23b-hexadecahydro-1H,9H-8,11-methanocyclopropa[4′,5′]cyclopenta[1′,2′:18,19][1,10,3,6]dioxadiazacyclononadecino[11,12-b]quinoxaline-9-carboxamide

Example 61 was prepared similarly to Example 59 substitutingIntermediate A10 for Intermediate A9 in Step 5. The TFA salt of Example61 was isolated. Analytic HPLC RetTime: 9.28 min. LCMS-ESI (m/z): [M+H]⁺calcd for C₄₃H₅₇F₄N₆O₉S: 909.38. found: 909.59. ¹H NMR (400 MHz, CD₃OD)(9.28 (s, 1H); 7.95 (d, J=9.2 Hz, 1H); 7.33 (dd, J=9.2, 2.4 Hz, 1H);7.23 (d, J=2.4 Hz, 1H); 6.0 (br s, 1H); 5.83 (br s, 1H); 5.83 (td,J_(H-F)=55 Hz, J=6 Hz, 1H); 4.94 (d, J=7.6 Hz, 1H); 4.61 (d, J=7.6 Hz,1H); 4.34 (d, J=7.6 Hz, 1H); 4.32 (br s, 1H); 4.18 (m, 1H); 3.97 (s,3H); 2.63-2.47 (m, 2H); 2.28-2.17 (m, 1H); 2.12-1.96 (m, 4H); 1.83-1.26(m, 14H); 1.53 (s, 3H); 1.19 (t, J=7.2 Hz, 3H); 1.08 (s, 9H); 0.94-0.88(m, 2H); 0.62-0.48 (m, 2H).

Example 62 Preparation of(1aS,2aR,6S,9S,10S,11R,23aR,23bS)-6-tert-butyl-N-[(1R,2R)-1-[(cyclopropylsulfonyl)carbamoyl]-2-(difluoromethyl)cyclopropyl]-19,19-difluoro-15-methoxy-10-methyl-4,7-dioxo-1a,2,2a,4,5,6,7,10,11,19,20,21,22,23,23a,23b-hexadecahydro-1H,9H-8,11-methanocyclopropa[4′,5′]cyclopenta[1′,2′:18,19][1,10,3,6]dioxadiazacyclononadecino[11,12-b]quinoxaline-9-carboxamide

Step 1. Preparation of Example 62-1: HATU (214 mg, 0.563 mmol, Oakwood)and DIPEA (0.30 mL, 1.72 mmol) were added to a mixture of 46-2 (186 mg,0.428 mmol) and Intermediate D16 (157 mg, 0.508 mmol) in 10 mL ofacetonitrile under argon. After stirring overnight, the reaction mixturewas concentrated under reduced pressure and the resulting residue waspurified by silica gel chromatography (0-30% ethyl acetate in hexanes)to yield Intermediate 62-1. LCMS-ESI (m/z): [M+H]⁺ calcd forC₃₉H₅₃F₂N₄O₇: 727.38. found: 727.51.

Step 2. Preparation of 62-2: A mixture of 62-1 (275 mg, 0.378 mmol) andZhan 1B catalyst (34 mg, 0.046 mmol, Strem) in 75 mL of DCE wasdeoxygenated with argon for 17 minutes. The mixture was then heated atreflux for 80 minutes. An additional 8 mg of Zhan 1B catalyst was addedand mixture stirred at reflux for twenty minutes. After cooling to roomtemperature, reaction mixture was concentrated in vacuo. The resultingresidue was purified by silica gel chromatography (0-25% ethyl acetatein hexanes) to yield intermediate 62-2. LCMS-ESI (m/z): [M+H]⁺ calcd forC₃₇H₄₉F₂N₄O₇: 699.35. found: 669.50.

Step 3. Preparation of mixture of 62-3: Palladium on carbon (10 wt % Pd,60 mg, 0.057 mmol) was added to a solution of 62-2 (207 mg, 0.297 mmol)in 7 mL of ethanol. The atmosphere was replaced with hydrogen andmixture was stirred overnight. The reaction was filtered over Celite,washing with ethanol. Filtrate was concentrated in vacuo to yieldintermediate 62-3, which was used in the next step without furtherpurification. LCMS-ESI (m/z): [M+H]⁺ calcd for C₃₇H₅₁F₂N₄O₇: 701.36.found: 701.65.

Step 4. Preparation of 62-4: TFA (1.6 mL, 20.9 mmol) was added slowly toa solution of 62-3 (202 mg, 0.289 mmol) in 4.5 mL of dichloromethane.After 3.5 hours, mixture was concentrated under reduced pressure to neardryness. Resulting residue was taken up in 30 mL of ethyl acetate,washed with 20 mL of water, 20 mL of sat. NaHCO_(3 (aq)), and separated.Aqueous layers were extracted with ethyl acetate (3×20 mL). Combinedorganics were washed with 30 mL of brine, dried over anhydrous MgSO₄,filtered, and concentrated in vacuo to yield intermediate 62-4, whichwas used in the next step without further purification. LCMS-ESI (m/z):[M+H]⁺ calcd for C₃₃H₄₃F₂N₄O₇: 645.30. found: 645.53.

Step 5. Preparation of Example 62: HATU (113 mg, 0.297 mmol, Oakwood)and DIPEA (0.17 mL, 0.978 mmol) were added to a mixture of 62-4 (120 mg,0.186 mmol) and Intermediate A9 (110 mg, 0.379 mmol) in 6 mL ofacetonitrile under argon. After stirring for overnight, reaction mixturewas taken up in 30 mL of ethyl acetate and washed with 20 mL of 1 Naqueous HCl. The aqueous layer was extracted three times with ethylacetate. Combined organics were washed with 50% brine, dried overanhydrous Na₂SO₄, filtered, and concentrated in vacuo. The resultingresidue was purified by silica gel chromatography (0-50% ethyl acetatein hexanes) and reverse phase prep HPLC (50-100% acetonitrile in water,with 0.1% trifluoroacetic acid buffer) to yield the trifluoroacetic acidsalt of Example 62. Analytic HPLC RetTime: 9.03 min. LCMS-ESI (m/z):[M+H]⁺ calcd for C₄₁H₅₃F₄N₆O₉S: 881.35. found: 881.57. ¹H NMR (400 MHz,CD₃OD): δ 9.27 (s, 1H), 7.94 (d, J=8.8 Hz, 1H), 7.33 (dd, J=9.2, 2.8 Hz,1H), 7.27 (d, J=2.8 Hz, 1H), 5.84 (td, J_(H-F)=56 Hz, J=6.8 Hz, 1H),5.75 (d, J=3.6 Hz, 1H), 4.94 (d, J=7.2 Hz, 1H), 4.55 (d, J=7.2 Hz, 1H),4.35 (d, J=12 Hz, 1H), 4.32 (s, 1H), 4.22-4.16 (dd, J=12, 4 Hz, 1H),3.97 (s, 3H), 3.01-2.94 (m, 1H), 2.81-2.72 (m, 1H), 2.66-2.40 (m, 1H),2.36-2.28 (m, 1H), 2.10-1.94 (m, 4H), 1.82-1.72 (m, 2H), 1.70-1.22 (m,10H), 1.14-1.02 (m, 7H), 1.10 (s, 9H), 0.61-0.49 (m, 2H).

Example 63 Preparation of(1aR,5S,8S,9S,10R,22aR)-5-tert-butyl-N-[(1R,2R)-2-(difluoromethyl)-1-{[(1-methylcyclopropyl)sulfonyl]carbamoyl}cyclopropyl]-9-ethyl-18,18-difluoro-14-methoxy-1a-methyl-3,6-dioxo-1,1a,3,4,5,6,9,10,18,19,20,21,22,22a-tetradecahydro-8H-7,10-methanocyclopropa[18,19][1,10,3,6]dioxadiazacyclononadecino[11,12-b]quinoxaline-8-carboxamide

Step 1. Preparation of 63-1: Amine hydrochloride 17-2 (500 mg, 1.03mmol) was combined with intermediate mixture D17 (378.5 mg, 1.34 mmol),DIPEA (1.8 mL, 10.3 mmol) and DMF (3 mL). HATU (587.1 mg, 1.55 mmol) wasthen added to the reaction mixture, which was stirred at roomtemperature for 18 hrs. Reaction mixture was then diluted with water (20mL) and 1N HCl (10.5 mL) and taken up into methylene chloride (20 mL).Organics were separated and aqueous layer was extracted three times withmethylene chloride (10 mL). Combined organics were then washed withbrine, dried over MgSO₄, filtered, and concentrated in vacuo. Cruderesidue was then purified via silica gel chromatography to give 63-1 asa 1:1 diastereomeric mixture. LCMS-ESI (m/z): [M+H]⁺ calcd forC₃₈H₅₃F₂N₄O₇: 715.4. found: 715.4.

Step 2. Preparation of 63-2 and 63-3: Diastereomeric mixture 63-1 (496mg, 0.695 mmol) and Zhan 1B catalyst (53.8 mg, 0.0695 mmol, Strem) weredissolved in 140 mL of anhydrous DCE and sparged with N₂ for 30 minutes.The mixture was then heated to 100° C. for 90 minutes, and an additionalportion of Zhan 1B catalyst was added (54 mg, 0.695 mmol, Strem).Reaction was then cooled to room temperature and concentrated in vacuo.The resulting residue was purified via silica gel chromatography (0% to40% ethyl acetate in hexanes) to yield single diastereomers 63-2 (earlyeluting fraction) and 63-3 (late eluting fraction). Early elutingfraction: LCMS-ESI (m/z): [M+H]⁺ calcd for C₃₆H₄₉F₂N₄O₇: 687.4. found:687.2 Late eluting fraction: LCMS-ESI (m/z): [M+H]⁺ calcd forC₃₆H₄₉F₂N₄O₇: 687.4. found: 687.3.

Step 3. Preparation of 63-4: Palladium on carbon (10% w/w, 155 mg) wasadded to a solution of 63-2 (155 mg, 0.226 mmol) in a ethanol (3 mL).Mixture was stirred under an atmosphere of hydrogen for 1 hr and wasthen filtered through a plug of Celite, and washed with ethyl acetate.Filtrate was concentrated under reduced pressure to yield 63-4, whichwas used in the next step without further purification. LCMS-ESI (m/z):[M+H]⁺ calcd for C₃₆H₅₁F₂N₄O₇: 689.4. found: 689.3.

Step 6. Preparation of 63-5: Intermediate 63-4 (153.5 mg, 0.222 mmol)was dissolved in a mixture of 1:1 TFA:DCM (6 mL) and stirred at roomtemperature for 3 hrs. Reaction mixture was then concentrated in vacuoto give 63-5, which was used in the subsequent step without furtherpurification. LCMS-ESI⁺ (m/z): [M+H]⁺ calcd for C₃₂H₄₄N₄O₇: 633.3.found: 633.2.

Step 7. Preparation of Example 63: HATU (99.2 mg, 0.261 mmol) and DIPEA(271 μL, 2.1 mmol) were added to a mixture of 63-5 (140.5 mg, 0.222mmol) and A10 (100 mg, 0.316 mmol) in 1 mL of DMF. After stirringovernight at room temperature, reaction mixture was poured into water,acidified to pH 1 with 1 N aqueous HCl, and extracted three times withmethylene chloride (15 mL). Combined organics were washed with water,brine, dried over MgSO₄, filtered, and concentrated under reducedpressure. The resulting residue was purified by reverse phase prep HPLC(5-100% acetonitrile in water, with 0.1% trifluoroacetic acid buffer) toafford Example 63. Analytic HPLC RetTime: 8.951 min. LCMS-ESI⁺ (m/z):[M+H]⁺ calcd for C₄₁H₅₅F₄N₆O₉S: 883.4. found: 883.2. ¹H NMR (400 MHz,CD₃OD) δ 7.96 (d, J=9.2 Hz, 1H), 7.33 (dd, J=9.2, 2.8 Hz, 1H), 7.23 (d,J=2.7 Hz, 1H), 6.03 (d, J=3.9 Hz, 1H), 5.80 (td, J=55.8, 6.7 Hz, 1H),4.61 (d, J=6.9 Hz, 1H), 4.46 (d, J=12.2 Hz, 1H), 4.26-4.14 (m, 2H),4.01-3.91 (m, 3H), 2.65-2.47 (m, 2H), 2.11-1.85 (m, 5H), 1.84-1.61 (m,3H), 1.61-1.46 (m, 10H), 1.46-1.32 (m, 3H), 1.33-1.17 (m, 4H), 1.09 (d,J=15.9 Hz, 10H), 1.04-0.95 (m, 1H), 0.94-0.84 (m, 2H), 0.21-0.12 (m,1H).

Example 64 Preparation of(1aS,5S,8S,9S,10R,22aS)-5-tert-butyl-N-[(1R,2R)-2-(difluoromethyl)-1-{[(1-methylcyclopropyl)sulfonyl]carbamoyl}cyclopropyl]-9-ethyl-18,18-difluoro-14-methoxy-1a-methyl-3,6-dioxo-1,1a,3,4,5,6,9,10,18,19,20,21,22,22a-tetradecahydro-8H-7,10-methanocyclopropa[18,19][1,10,3,6]dioxadiazacyclononadecino[11,12-b]quinoxaline-8-carboxamide

Example 64 was prepared in a similar fashion to Example 63, substitutinglate eluting 63-3 for early eluting 63-2 in Step 3. Example 64 was thenisolated. Analytic HPLC RetTime: 8.535 min. LCMS-ESI⁺ (m/z): [M+H]⁺calcd for C₄₁H₅₇F₂N₆O₉S: 883.4. found: 883.3. ¹H NMR (400 MHz, CD₃OD) δ7.97 (d, J=8.9 Hz, 1H), 7.45-7.16 (m, 2H), 5.97-5.52 (m, 2H), 4.74 (d,J=7.6 Hz, 1H), 4.50-4.16 (m, 1H), 4.06-3.86 (m, 5H), 2.77-2.57 (m, 1H),2.51-2.18 (m, 2H), 2.16-1.86 (m, 5H), 1.75-1.32 (m, 16H), 1.33-1.03 (m,14H), 1.02-0.76 (m, 2H), 0.42-−0.09 (m, 1H).

Example 65 Preparation of(1aR,5S,8S,9S,10R,22aR)-5-tert-butyl-N-[(1R,2R)-2-(difluoromethyl)-1-{[(1-methylcyclopropyl)sulfonyl]carbamoyl}cyclopropyl]-18,18-difluoro-14-methoxy-3,6-dioxo-9-propyl-1,1a,3,4,5,6,9,10,18,19,20,21,22,22a-tetradecahydro-8H-7,10-methanocyclopropa[18,19][1,10,3,6]dioxadiazacyclononadecino[11,12-b]quinoxaline-8-carboxamide

Step 1. Preparation of Example 65: To a solution of 60-6 (52 mg, 82μmol) and Intermediate A10 (37.5 mg, 123 μmol) in MeCN (411 μL) wasadded HATU (47.5 mg, 123 μmol) followed by DIPEA (73 μL, 411 μmol) at rtunder an argon atmosphere. After 20 h, the reaction mixture wasconcentrated in vacuo, was purified by preparatory HPLC (Gemini 5u C18110 Å column, 5-100% MeCN/H₂O, 0.1% trifluoroacetic acid modifier) andwas lyophilized to afford Example 65 as a TFA salt. Analytic HPLCRetTime: 8.99 min. LCMS-ESI⁺ (m/z): [M+H]⁺ calcd for C₄₁H₅₅F₄N₆O₉S:883.36. found: 883.60. ¹H NMR (400 MHz, CD₃OD) δ 9.26 (s, 1H), 7.95 (d,J=9.1 Hz, 1H), 7.33 (dd, J=9.2, 2.8 Hz, 1H), 7.22 (d, J=2.8 Hz, 1H),5.89 (d, J=3.2 Hz, 1H), 5.81 (td, J_(H-F)=55.5 Hz, J=6.5 Hz, 1H), 4.59(d, J=7.0 Hz, 1H), 4.40 (d, J=12.5 Hz, 1H), 4.36 (s, 1H), 4.17 (dd,J=12.2, 3.8 Hz, 1H), 3.97 (s, 3H), 3.73-3.66 (m, 1H), 2.73-2.64 (m, 1H),2.63-2.45 (m, 1H), 2.01 (br s, 3H), 1.85-1.62 (m, 4H), 1.62-1.53 (m,3H), 1.51 (s, 3H), 1.48-1.22 (m, 5H), 1.08 (s, 9H), 1.01 (app t, J=7.3Hz, 4H), 0.94-0.87 (m, 2H), 0.80-0.69 (m, 1H), 0.50 (d, J=7.1 Hz, 1H).

Example 66 Preparation of(4aR,8S,11S,12S,13R,25aR)-8-tert-butyl-N-[(1R,2R)-1-[(cyclopropylsulfonyl)carbamoyl]-2-(difluoromethyl)cyclopropyl]-12-ethyl-17-methoxy-6,9-dioxo-2,3,4,4a,6,7,8,9,12,13,21,22,23,24,25,25a-hexadecahydro-1H,11H-10,13-methanoquinoxalino[2,3-k][1,10,3,6]benzodioxadiazacyclononadecine-11-carboxamide

Step 1. Preparation of 66-1 and 66-2. To a solution of Intermediate 70-3(283 mg, 0.42 mmol) in CH₂Cl₂ (5 mL) was added TMSOTf (380 μL, 2.1mmol). After stirring for 2 h, the reaction mixture was poured intostirring 1 N NaOH (12 mL). The mixture was transferred to a sept funnel,acidified to pH 3 with 1N HCl, extracted with CH₂Cl₂, dried overmagnesium sulfate, and concentrated. The crude residue was purified bysilica gel chromatography (0-10% MeOH/EtOAc) to yield a mixture of 66-1and 66-2. LCMS-ESI (m/z): [M+H]⁺ calcd for C₃₄H₄₇N₄O₇: 623.34. found:623.66.

Step 2. Preparation of 66-3 and 66-4. To a solution of 66-1 and 66-2 (58mg, 0.09 mmol), intermediate A9 (32 mg, 0.11 mmol), TBTU (42 mg, 0.13mmol) and DMAP (16 mg, 0.14 mmol) in DMF (3 mL) was added DIPEA (47 μL,0.27 mmol) and the reaction was stirred at rt for 23 h. The reaction wasquenched with water, diluted with EtOAc, washed with sat. NaHCO₃, brine,dried over magnesium sulfate, and concentrated. The crude material waspurified by reverse phase HPLC (Gemini, 30-85% ACN/H₂O+0.1% TFA) andlyophilized to give the TFA salt of Intermediate 66-3 and 66-4 mixture.LCMS-ESI (m/z): [M+H]⁺ calcd for C₄₂H₅₇F₂N₆O₉S: 859.39. found: 859.65.

Step 3. Preparation of Example 66: To 66-3 and 66-4 (5 mg, 0.005 mmol)that was taken up in EtOH (2 mL) and treated with Pd/C (10%, 5 mg). Theatmosphere was replaced with hydrogen and stirred at rt for 2.5 h. Thereaction was filtered over Celite, washed with EtOAc and concentrated.The residue was purified by silica gel chromatography (0-10% MeOH/EtOAc)and lyophilized to give the parent compound. Analytical HPLC RetTime:9.15 min. LCMS-ESI⁺ (m/z): [M+H]⁺ calcd for C₄₂H₅₉F₂N₆O₉S: 862.01.found: 862.37. ¹H NMR (400 MHz, CD₃OD) δ 7.94-7.73 (m, 1H), 7.25 (m,1H), 6.87 (d, J=9.8 Hz, 1H), 6.05 (m, 2H), 4.83-4.74 (m, 1H), 4.70 (d,J=7.6 Hz, 1H), 4.52-4.28 (m, 2H), 4.16 (m, 2H), 4.05-3.86 (m, 4H),3.86-3.45 (m, 4H), 3.22-3.00 (m, 1H), 2.89 (s, 1H), 2.77-2.55 (m, 1H),2.25 (t, J=7.3 Hz, 1H), 2.09-0.81 (m, 35H).

Example 67 Preparation of(1aR,5S,8S,9S,10R,22aR)-5-tert-butyl-N-[(1R,2S)-2-(2,2-difluoroethyl)-1-{[(1-methylcyclopropyl)sulfonyl]carbamoyl}cyclopropyl]-9-ethyl-14-methoxy-3,6-dioxo-1,1a,3,4,5,6,9,10,18,19,20,21,22,22a-tetradecahydro-8H-7,10-methanocyclopropa[18,19][1,10,3,6]dioxadiazacyclononadecino[11,12-b]quinoxaline-8-carboxamide

Example 67 was prepared similarly to Example 1 substituting IntermediateA8 for Intermediate A10 in Step 8. The TFA salt of Example 67 wasisolated. Analytic HPLC RetTime: 8.85 min. LCMS-ESI⁺ (m/z): [M+H]⁺ calcdfor C₄₁H₅₇F₂N₆O₉S: 847.99. found: 847.64. ¹H NMR (400 MHz, CD₃OD) (9.00(s, 1H); 7.79 (d, J=9.2 Hz, 1H); 7.23 (dd, J=9.2, 2.4 Hz, 1H); 7.15 (d,J=2.4 Hz, 1H); 5.89 (tt, J_(H-F)=54 Hz, J=4.4 Hz, 1H); 5.89 (br s, 1H);4.61 (d, J=7.2 Hz, 1H); 4.39 (br s, 1H); 4.37 (d, J=9.2 Hz, 1H); 4.16(dd, J=9.2 Hz, 7.2 Hz, 1H); 3.92 (s, 3H); 3.78-3.72 (m, 1H); 3.10-2.88(m, 1H); 2.86-2.74 (td, J=12, 4.4 Hz, 1H); 2.62-2.53 (m, 1H); 2.18-2.04(m, 1H); 1.88-1.46 (m, 14H); 1.53 (s, 3H); 1.28-1.20 (m, 4H); 1.10 (s,9H); 1.02-0.96 (m, 2H); 0.96-0.86 (m, 2H); 0.78-0.67 (m, 1H); 0.54-0.47(m, 1H).

Example 68 Preparation of(4aR,8S,11S,12S,13R,25aS)-8-tert-butyl-N-[(1R,2R)-1-[(cyclopropylsulfonyl)carbamoyl]-2-(difluoromethyl)cyclopropyl]-21,21-difluoro-17-methoxy-12-methyl-6,9-dioxo-2,3,4,4a,6,7,8,9,12,13,21,22,23,24,25,25a-hexadecahydro-1H,11H-10,13-methanoquinoxalino[2,3-k][1,10,3,6]benzodioxadiazacyclononadecine-11-carboxamide

Step 1. Preparation of 68-1 and 68-2 (mixture): TMSOTf (0.6 mL, 3.3mmol) was added to a solution of intermediate 62-3 (424 mg, 0.606 mmol)in 7 mL of dichloromethane at room temperature. After 1 hour, anadditional 0.2 mL of TMSOTf was added. After a total of three hours,reaction mixture was concentrated to yield a mixture of 68-1 and 68-2isomers, which was used in the next step without further purification.LCMS-ESI (m/z): [M+H]⁺ calcd for C₃₃H₄₃F₂N₄O₇: 645.30. found: 645.49.

Step 2. Preparation of 68-3 and 68-4 (mixture): HATU (209 mg, 0.550mmol, Oakwood) and DIPEA (0.25 mL, 1.43 mmol) were added to the mixtureof 68-1 and 68-2 from the previous step (176 mg, 0.273 mmol) andIntermediate A9 (161 mg, 0.555 mmol) in 4 mL of acetonitrile and 2 mL ofDMF under argon. After one hour, an additional 100 mg of Intermediate A9was added. After two hours, reaction mixture was taken up in 30 mL ofethyl acetate and washed with 20 mL of 1 N aqueous HCl. The aqueouslayer was extracted three times with ethyl acetate. Combined organicswere washed with 50% brine, dried over anhydrous Na₂SO₄, filtered, andconcentrated in vacuo. The resulting residue was purified by silica gelchromatography (0-50% ethyl acetate in hexanes) and reverse phase prepHPLC (50-100% acetonitrile in water, with 0.1% trifluoroacetic acidbuffer) to yield the trifluoroacetic acid salts of a mixture of 68-3 and68-4. LCMS-ESI⁺ (m/z): [M+H]⁺ calcd for C₄₁H₅₃F₄N₆O₉S: 881.35. found:881.50.

Step 3. Preparation of Example 68: Palladium on carbon (10 wt % Pd, 2mg, 0.0019 mmol) was added to a solution of the mixture of 68-3 and 68-4from the previous step (4.5 mg, 0.0045 mmol) in 1 mL of ethanol. Theatmosphere was replaced with hydrogen and mixture was stirred for twohours. The reaction was filtered over Celite, washing with ethanol.Filtrate was concentrated in vacuo to yield Example 68. Analytic HPLCRetTime: 8.81 min. LCMS-ESI (m/z): [M+H]⁺ calcd for C₄₁H₅₅F₄N₆O₉S:883.36. found: 883.64. ¹H NMR (400 MHz, CD₃OD): δ 7.94 (d, J=10.4 Hz,1H), 7.34-7.30 (m, 2H), 6.13 (td, J_(H-F)=57 Hz, J=6.8 Hz, 1H),5.88-5.84 (m, 1H), 4.62 (d, J=7.6 Hz, 1H), 4.38-4.30 (m, 2H), 4.20-4.05(m, 2H), 3.98 (s, 3H), 2.87-2.76 (m, 2H), 2.34-2.16 (m, 2H), 1.92-1.54(m, 6H), 1.46-1.36 (m, 3H), 1.34-1.12 (m, 8H), 1.20 (d, J=7.6 Hz, 3H),1.08-0.96 (m, 4H), 1.04 (s, 9H), 0.93-0.78 (m, 4H).

Example 69 Preparation of(1aR,5S,8S,9S,10R,22aR)-5-tert-butyl-N-[(1R,2R)-2-(difluoromethyl)-1-{[(1-methylcyclopropyl)sulfonyl]carbamoyl}cyclopropyl]-14-ethoxy-9-ethyl-3,6-dioxo-1,1a,3,4,5,6,9,10,18,19,20,21,22,22a-tetradecahydro-8H-7,10-methanocyclopropa[18,19][1,10,3,6]dioxadiazacyclononadecino[11,12-b]quinoxaline-8-carboxamide

Step 1. Preparation of 69-2. Quinoxalinol 55-1 (54 mg, 0.086 mmol) wassuspended in ACN (2 mL) and treated with Cs₂CO₃ (84 mg, 0.259 mmol) andbromoethane (0.032 mL, 0.432 mmol). The reaction mixture was stirred atRT for 16 h. The reaction was filtered and the crude material waspurified by flash column chromatography to afford 69-2. LCMS-ESI (m/z):[M+H]⁺ calcd for C₃₆H₅₂N₄O₇: 652.38. found: 653.41.

Step 2. Preparation of 69-3. Intermediate 69-2 (0.086 mmol theoretical)was treated with DCM (10 mL) and TMSOTf (1.0 mL) at RT. After 1 h, thereaction was complete determined by LCMS. The reaction was concentratedunder reduced pressure to afford 69-3, which was carried on withoutfurther purification. LCMS-ESI (m/z): [M+H]⁺ calcd for C₃₂H₄₄N₄O₇:596.32. found: 597.38.

Step 3. Preparation of Example 69. Carboxcylic acid 69-3 (0.0.086 mmoltheoretical) was treated with intermediate A10 (40 mg, 0.130 mmol), TBTU(47 mg, 0.147 mmol), DMAP (18 mg, 0.147 mmol), DCM (3 mL) and DIPEA(0.075 mL, 0.432 mmol). The reaction mixture was stirred at RT for 20 h,then concentrated under reduced pressure and purified by reverse phaseHPLC to afford Example 69 as a TFA salt. LCMS-ESI (m/z): [M+H]⁺ calcdfor C₄₁H₅₆F₂N₆O₉S: 846.38. found: 847.75.

Example 70 Preparation of(1aS,2aR,6S,9S,10S,11R,23aR,23bS)-6-tert-butyl-N-[(1R,2R)-1-[(cyclopropylsulfonyl)carbamoyl]-2-(difluoromethyl)cyclopropyl]-10-ethyl-15-methoxy-4,7-dioxo-1a,2,2a,4,5,6,7,10,11,19,20,21,22,23,23a,23b-hexadecahydro-1H,9H-8,11-methanocyclopropa[4′,5′]cyclopenta[1′,2′:18,19][1,10,3,6]dioxadiazacyclononadecino[11,12-b]quinoxaline-9-carboxamide

Step 1. Preparation of 70-1: To a solution of 1-2 (575 mg, 1.41 mmol),D12 (410 mg, 1.26 mmol) and HATU (696 mg, 1.80 mmol) in DMF (12 mL) wasadded DIPEA (1.0 mL, 5.64 mmol) and the reaction was stirred at rt.After stirring for 2 h, additional HATU (350 mg, 0.92 mmol) and DIPEA(0.5 mL, 2.8 mmol) was added to the reaction, and the mixture wasstirred for 14 h. The reaction was quenched with sat. NaHCO₃ solutionand extracted with EtOAc, washed subsequently with brine, dried overmagnesium sulfate and concentrated. The crude product was purified bysilica gel chromatography (10-30% EtOAc/hexanes) to yield intermediate70-1. LCMS-ESI (m/z): [M+H]⁺ calcd for C₃₈H₅₄ClN₄O₇: 713.37. found:713.95.

Step 2. Preparation of 70-2: To a solution of 70-1 (542 mg, 0.76 mmol),TEA (0.16 mL, 1.14 mmol) and potassium vinyltrifluoroborate (153 mg,1.14 mmol) in EtOH (10 mL) was added PdCl₂(dppf) (62 mg, 0.08 mmol). Thereaction was degassed with N₂ for 10 min and heated to 80° C. for 1 h.The reaction was quenched with sat. NaHCO₃ solution and extracted withEtOAc, washed subsequently with brine, dried over magnesium sulfate andconcentrated. The residue was purified using silica gel chromatography(0-20% EtOAc/hexanes) to give intermediate 70-2. LCMS-ESI⁺ (m/z): [M+H]⁺calcd for C₄₀H₅₇N₄O₇: 705.42. found: 705.05.

Step 3 and 4. Preparation of 70-3: To a solution of 70-2 (470 mg, 0.66mmol) in DCE (100 mL) was added Zhan 1B catalyst (49 mg, 0.07 mmol) andthe reaction was degassed for 30 minutes with N₂. The reaction washeated to 100° C. for 1 h, allowed to cool to rt and concentrated. Thecrude product was purified by silica gel chromatography to give product(358 mg; LCMS-ESI⁺ (m/z): [M+H]⁺ calcd for C₃₈H₅₃N₄O₇: 677.39. found:677.52) that was taken up in EtOH (6 mL) and EtOAc (2 mL) and treatedwith Pd/C (10%, 350 mg). The atmosphere was replaced with hydrogen andstirred at rt for 1.5 h. The reaction was filtered over Celite, washedwith EtOAc and concentrated (358 mg intermediate 70-3) that was usedsubsequently without further purification. LCMS-ESI⁺ (m/z): [M+H]⁺ calcdfor C₃₈H₅₅N₄O₇: 679.41. found: 679.44.

Step 5. Preparation of 70-4: To a solution of 70-3 (100 mg, 0.15 mmol)in DCM (1 mL) was added TFA (1 mL) and stirred at rt for 2 h. Thereaction was diluted with EtOAc, washed with H₂O, basicified to pH 7with sat. NaHCO₃ solution, dried over magnesium sulfate, andconcentrated to give a residue of intermediate 70-4 that was usedsubsequently without further purification LCMS-ESI⁺ (m/z): [M+H]⁺ calcdfor C₃₄H₄₇N₄O₇: 623.34. found: 623.44.

Step 6. Preparation of Example 70: To a solution of 70-4 (94 mg, 0.15mmol), intermediate A9 (65 mg, 0.22 mmol), TBTU (87 mg, 0.27 mmol) andDMAP (27 mg, 0.22 mmol) in DCM (3 mL) was added DIPEA (0.13 mL, 0.75mmol) and the reaction was stirred at rt for 2 h. The reaction wasquenched with water, diluted with EtOAc, washed with sat. NaHCO₃, brine,dried over magnesium sulfate, and concentrated. The crude material waspurified by reverse phase HPLC (Gemini, 30-85% ACN/H₂O+0.1% TFA) andlyophilized to give Example 70 (23 mg) as a TFA salt.

Analytical HPLC RetTime: 9.32 min. LCMS-ESI⁺ (m/z): [M+H]⁺ calcd forC₄₂H₅₇F₂N₆O₉S: 859.39. found: 859.54. ¹H NMR (400 MHz, CD₃OD) δ 9.31 (s,1H), 7.83 (d, J=9.1 Hz, 1H), 7.26 (dd, J=9.1, 2.8 Hz, 1H), 7.20 (d,J=2.7 Hz, 1H), 6.09-5.68 (m, 2H), 5.51 (s, 1H), 5.07-4.97 (m, 1H),4.70-4.55 (m, 1H), 4.42-4.29 (m, 2H), 4.22 (dd, J=12.0, 4.1 Hz, 1H),3.96 (s, 2H), 3.75 (t, J=6.7 Hz, 2H), 3.02 (m, 2H), 2.93-2.67 (m, 1H),2.56 (m, 1H), 2.13-1.04 (m, 30H), 1.00 (d, J=6.6 Hz, 1H), 0.90 (m, 3H),0.65-0.46 (m, 2H).

Example 71 Preparation of(4aR,8S,11S,12S,13R,25aR)-8-tert-butyl-N-[(1R,2R)-1-[(cyclopropylsulfonyl)carbamoyl]-2-(difluoromethyl)cyclopropyl]-17-methoxy-12-methyl-6,9-dioxo-2,3,4,4a,6,7,8,9,12,13,21,22,23,24,25,25a-hexadecahydro-1H,11H-1,3:10,13-dimethanoquinoxalino[2,3-k][1,10,3,6]benzodioxadiazacyclononadecine-11-carboxamideand

Step 1: To a solution of amine 18-2 (315 mg, 0.80 mmol), DIPEA (350 μL,2.0 mmol) and a 1:1 mixture of acids D19 (270 mg, 0.80 mmol) in MeCN (8mL) was added HATU (400 mg, 1.05 mmol). The resulting solution wasstirred for 2.5 h at r.t., at which time it was diluted with EtOAc (50mL) and 0.2 N aqueous HCl (30 mL). The phases were separated, and theorganic phase was dried over MgSO₄, filtered, and concentrated to afforda crude residue. Purification by silica gel chromatography (10% to 30%EtOAc in hexanes) provided 474 mg of a colorless oil that was useddirectly in the next step.

Step 2: A suspension of the product from step 1 (474 mg, ca. 0.65 mmol),PdCl₂(dppf)*CH₂Cl₂ (40 mg, 0.049 mmol) and potassiumvinyltrifluoroborate (189 mg, 1.41 mmol) in EtOH (8 mL) was sparged withAr for several minutes and Et₃N (200 μL, 1.4 mmol) was added. Theresulting mixture was heated under Ar to 75° C. via oil bath. Afterstirring 2.25 h, the reaction mixture was cooled to r.t. and was dilutedwith EtOAc (35 mL) and half-saturated brine (20 mL). The phases wereseparated, and the organic phase was dried over Na₂SO₄, filtered, andconcentrated to afford a crude residue. Purification by silica gelchromatography provided a yellow oil that was used directly in the nextstep.

Step 3: A solution of the product from Step 3 (395 mg, 0.56 mmol) in1,2-DCE (180 mL) was sparged with Ar for 10 min. Zhan 1B metathesiscatalyst (61 mg, 0.083 mmol) was then added as a solution in DCE (4 mL),and the resulting solution was heated to 85° C. After stirring 1.75 h,the reaction mixture was cooled to ambient temperature, concentratedonto silica gel (5 g), and purified by silica gel chromatography (10 to15 to 25% EtOAc in hexanes) to afford 116 mg of a fast-eluting productand 84 mg of a slow-eluting product.

Step 4-5 (fast-eluting diastereomer): The fast-eluting product from Step3 was dissolved in 1:1 EtOAc:EtOH (4 mL). Pd/C (10 wt. % Pd, 45 mg) wasadded, and the reaction vessel was purged twice with 1 atm H₂. Thereaction mixture was stirred for 2.5 h under 1 atm H₂ and was thenfiltered through celite with EtOAc to afford a crude residue. Thisresidue was dissolved in CH₂Cl₂ (1 mL) and was treated with TFA (2 mL).After stirring 2 h, the reaction mixture was concentrated in vacuo andwas partitioned between EtOAc (15 mL) and 15% saturated aqueous NaHCO₃(10 mL). The phases were separated, and the organic phase was washedwith brine (10 mL), dried over Na₂SO₄, and filtered to provide 71-1.LCMS-ESI (m/z): [M+H]⁺ calcd for C₃₄H₄₇N₄O₇: 623.3. found: 623.2.

Step 4-5 (slow-eluting diastereomer): The slow-eluting product from Step3 was dissolved in EtOAc (1 mL) and EtOH (7 mL). Pd/C (10 wt. % Pd, 85mg) was added, and the reaction vessel was purged twice with 1 atm H₂.The reaction mixture was stirred for 3 h under 1 atm H₂ and was thenfiltered through celite with EtOAc to afford a crude residue. Thisresidue was dissolved in CH₂Cl₂ (1 mL) and was treated with TFA (2 mL).After stirring 2 h, the reaction mixture was concentrated in vacuo andwas partitioned between EtOAc (15 mL) and 15% saturated aqueous NaHCO₃(10 mL). The phases were separated, and the organic phase was washedwith brine (10 mL), dried over Na₂SO₄, and filtered to provide 71-2.LCMS-ESI (m/z): [M+H]⁺ calcd for C₃₄H₄₇N₄O₇: 623.3. found: 623.2.

Step 6: Preparation of Example 71: To a suspension of acid 71-1 (49 mg,0.079 mmol) and amine hydrochloride A9 (41 mg, 0.14 mmol) in MeCN (1 mL)was added DIPEA (100 μL, 0.57 mmol). HATU (45 mg, 0.12 mmol) was addedto the resulting solution, and the reaction was stirred at rt for 14.5h. The reaction was then diluted with EtOAc (20 mL), 0.2 M aqueous HCl(10 mL) and brine (10 mL). The phases were separated and the aqueousphase was extracted with EtOAc (20 mL). The combined organic phase wasdried over Na₂SO₄, filtered, and concentrated to afford a crude residue.This residue was dissolved in CH₂Cl₂ and was concentrated onto 2 gsilica gel. Purification by silica gel chromatography (4% to 45% acetonein hexanes) provided an amorphous residue that was lyophilized fromwater and MeCN to provide Example 71. LCMS-ESI⁺ (m/z): [M+H]⁺ calcd forC₄₂H₅₇F₂N₆O₉S: 859.4. found: 859.1. ¹H NMR (400 MHz, CDCl₃) δ 10.13 (s,1H), 7.81 (d, J=9.1 Hz, 1H), 7.63 (s, 1H), 7.19 (dd, J=9.1, 2.8 Hz, 1H),7.09 (d, J=2.7 Hz, 1H), 5.97 (td, J=55.5, 6.9 Hz, 1H), 5.59-5.45 (m,2H), 4.96 (dd, J=14.4, 6.2 Hz, 1H), 4.51 (d, J=7.2 Hz, 1H), 4.42 (d,J=9.8 Hz, 1H), 4.13 (dt, J=12.0, 7.7 Hz, 2H), 3.93 (s, 3H), 2.99-2.63(m, 4H), 2.40-2.23 (m, 2H), 2.15-0.83 (m, 34H).

Example 72 Preparation of(4aS,8S,11S,12S,13R,25aS)-8-tert-butyl-N-[(1R,2R)-1-[(cyclopropylsulfonyl)carbamoyl]-2-(difluoromethyl)cyclopropyl]-17-methoxy-12-methyl-6,9-dioxo-2,3,4,4a,6,7,8,9,12,13,21,22,23,24,25,25a-hexadecahydro-1H,11H-1,3:10,13-dimethanoquinoxalino[2,3-k][1,10,3,6]benzodioxadiazacyclononadecine-11-carboxamide

Step 1: Preparation of Example 72: To a suspension of acid 71-2 (49 mg,0.079 mmol) and amine hydrochloride A9 (38 mg, 0.13 mmol) in MeCN (1 mL)was added DIPEA (100 μL, 0.57 mmol). HATU (41 mg, 0.11 mmol) was addedto the resulting solution, and the reaction was stirred at rt for 14.5h. The reaction was then diluted with EtOAc (20 mL), 0.2 M aqueous HCl(10 mL) and brine (10 mL). The phases were separated and the aqueousphase was extracted with EtOAc (20 mL). The combined organic phase wasdried over Na₂SO₄, filtered, and concentrated to afford a crude residue.This residue was dissolved in CH₂Cl₂ and was concentrated onto 2 gsilica gel. Purification by silica gel chromatography (4% to 45% acetonein hexanes) provided an amorphous residue that was lyophilized fromwater and MeCN to provide Example 72. LCMS-ESI⁺ (m/z): [M+H]⁺ calcd forC₄₂H₅₇F₂N₆O₉S: 859.4. found: 859.0. ¹H NMR (400 MHz, CDCl₃) δ 9.72 (s,1H), 9.36 (s, 1H), 7.86 (d, J=9.1 Hz, 1H), 7.28 (d, J=2.7 Hz, 1H),7.25-7.17 (m, 2H), 5.98-5.88 (m, 1H), 5.69 (td, J=55.4, 6.9 Hz, 1H),4.81-4.69 (m, 1H), 4.68-4.56 (m, 2H), 4.33 (d, J=10.1 Hz, 1H), 3.99 (s,3H), 3.35 (dd, J=9.7, 7.0 Hz, 1H), 3.24-3.13 (m, 1H), 2.97-2.87 (m, 1H),2.87-2.72 (m, 2H), 2.57-2.45 (m, 1H), 2.38-2.28 (m, 1H), 2.17-0.71 (m,34H).

Example 73 Preparation of(1aR,5S,8S,9S,10R,22aR)-5-tert-butyl-9-ethyl-14-methoxy-N-[(1R,2R)-2-methyl-1-{[(1-methylcyclopropyl)sulfonyl]carbamoyl}cyclopropyl]-3,6-dioxo-1,1a,3,4,5,6,9,10,18,19,20,21,22,22a-tetradecahydro-8H-7,10-methanocyclopropa[18,19][1,10,3,6]dioxadiazacyclononadecino[11,12-b]quinoxaline-8-carboxamide

Example 73 was prepared similarly to Example 1 substituting IntermediateA11 for Intermediate A10 in Step 8. The TFA salt of Example 73 wasisolated. Analytic HPLC RetTime: 8.72 min. LCMS-ESI⁺ (m/z): [M+H]⁺ calcdfor C₄₀H₅₇N₆O₉S: 797.98. found: 797.54. ¹H NMR (400 MHz, CD₃OD) δ 8.84(s, 1H); 7.79 (d, J=9.2 Hz, 1H); 7.22 (dd, J=9.2, 2.4 Hz, 1H); 7.13 (d,J=2.4 Hz, 1H); 5.87 (d, J=3.2 Hz, 1H); 4.57 (d, J=7.2 Hz, 1H); 4.39 (brs, 1H); 4.37 (br d, J=10 Hz, 1H); 4.15 (dd, J=12, 4 Hz, 1H); 3.92 (s,3H); 3.74 (m, 1H); 3.10-2.88 (m, 1H); 2.80 (td, J=12.4, 4 Hz, 1H); 2.58(m, 1H); 1.89-1.66 (m, 3H); 1.66-1.38 (m, 11H); 1.52 (s, 3H); 1.23 (t,J=7.2 Hz, 3H); 1.16 (d, J=6 Hz, 3H); 1.10 (s, 9H); 1.02-0.84 (m, 4H);0.78-0.66 (m, 1H); 0.55-0.20 (m, 1H).

Example 74 Preparation of(1aR,5S,8S,9S,10R,22aR)-5-tert-butyl-N-[(1R,2R)-2-(difluoromethyl)-1-{[(1-fluorocyclopropyl)sulfonyl]carbamoyl}cyclopropyl]-9-ethyl-14-methoxy-3,6-dioxo-1,1a,3,4,5,6,9,10,18,19,20,21,22,22a-tetradecahydro-8H-7,10-methanocyclopropa[18,19][1,10,3,6]dioxadiazacyclononadecino[11,12-b]quinoxaline-8-carboxamide

Example 74 was prepared similarly to Example 1 substituting IntermediateA12 for Intermediate A10 in Step 8. The TFA salt of Example 74 wasisolated. Analytic HPLC RetTime: 8.81 min. LCMS-ESI⁺ (m/z): [M+H]⁺ calcdfor C₃₉H₅₂F₃N₆O₉S: 837.35. found: 837.54. ¹H NMR (400 MHz, CD₃OD) (9.26(s, 1H); 7.79 (d, J=9.2 Hz, 1H); 7.22 (dd, J=9.2, 2.4 Hz, 1H); 7.14 (d,J=2.4 Hz, 1H); 5.89 (d, J=3.6 Hz, 1H); 5.82 (td, J_(H-F)=56 Hz, J=6.4Hz, 1H); 4.56, (d, J=7.2 Hz, 1H); 4.39 (s, 1H); 4.38 (d, J=12 Hz, 1H);4.16 (dd, J=12, 7.2 Hz, 1H); 3.92 (s, 3H); 3.78-3.72 (m, 1H); 3.10-2.89(m, 1H); 2.80 (td, J=12, 4 Hz, 1H); 2.63-2.54 (m, 1H); 2.02 (m, 2H);1.95-1.66 (m, 3H); 1.66-1.36 (m, 9H); 1.22 (t, J=7.2 Hz, 3H); 1.14-1.04(m, 2H); 1.09 (s, 9H); 1.04-0.92 (m, 2H); 0.78-0.68 (m, 1H); 0.57-0.46(m, 1H).

Example 75 Preparation of(1aR,5S,8S,9S,10R,22aR)-5-tert-butyl-N-[(1R,2R)-1-{[(1-chlorocyclopropyl)sulfonyl]carbamoyl}-2-(difluoromethyl)cyclopropyl]-9-ethyl-14-methoxy-3,6-dioxo-1,1a,3,4,5,6,9,10,18,19,20,21,22,22a-tetradecahydro-8H-7,10-methanocyclopropa[18,19][1,10,3,6]dioxadiazacyclononadecino[11,12-b]quinoxaline-8-carboxamide

Example 75 was prepared similarly to Example 1 substituting IntermediateA13 for Intermediate A10 in Step 8. The TFA salt of Example 75 wasisolated. Analytic HPLC RetTime: 8.89 min. LCMS-ESI⁺ (m/z): [M+H]⁺ calcdfor C₃₉H₅₂ClF₂N₆O₉S: 853.32. found: 853.94. ¹H NMR (400 MHz, CD₃OD)(9.24 (s, 1H); 7.79 (d, J=9.2 Hz, 1H); 7.22 (dd, J=9.2, 2.4 Hz, 1H);7.13 (d, J=2.4 Hz, 1H); 5.88 (d, J=3.2 Hz, 1H); 5.84 (td, J_(H-F)=55.6Hz, J=6.8 Hz, 1H); 4.57 (d, J=7.2 Hz, 1H); 4.39 (br s, 1H); 4.38 (d,J=12 Hz, 1H); 4.16 (dd, J=12, 7.2 Hz, 1H); 3.92 (s, 3H); 3.77-3.73 (m,1H); 3.00-2.88 (m, 1H); 2.86-2.75 (m, 1H); 2.64-2.54 (m, 1H); 2.10-1.90(m, 4H); 1.90-1.37 (m, 12H); 1.23 (t, J=7.2 Hz, 3H); 1.10 (s, 9H);1.02-0.96 (m, 2H); 0.78-0.64 (m, 1H); 0.56-0.45 (m, 1H).

Example 76 Preparation of(1aR,5S,8S,9S,10R,22aR)-5-tert-butyl-N-[(1R,2R)-2-(difluoromethyl)-1-{[(1-methylcyclopropyl)sulfonyl]carbamoyl}cyclopropyl]-18,18-difluoro-14-methoxy-1a,9-dimethyl-3,6-dioxo-1,1a,3,4,5,6,9,10,18,19,20,21,22,22a-tetradecahydro-8H-7,10-methanocyclopropa[18,19][1,10,3,6]dioxadiazacyclononadecino[11,12-b]quinoxaline-8-carboxamide

Step 1. Preparation of 76-1: HATU (502 mg, 1.32 mmol, Oakwood) and DIPEA(0.70 mL, 4.02 mmol) were added to a mixture of 46-2 (434 mg, 0.998mmol) and Intermediate D17 (350 mg, 1.24 mmol) in 16 mL of acetonitrileunder argon. After stirring overnight, the reaction mixture wasconcentrated under reduced pressure and the resulting residue waspurified by silica gel chromatography (0-25% ethyl acetate in hexanes)to yield 76-1. LCMS-ESI (m/z): [M+H]⁺ calcd for C₃₇H₅₁F₂N₄O₇: 701.36.found: 701.57.

Step 2. Preparation of 76-2 and 76-3: A diastereomeric mixture 76-1 (550mg, 0.786 mmol) and Zhan 1B catalyst (69 mg, 0.094 mmol, Strem) in 157mL of DCE was deoxygenated under argon for 25 minutes. The mixture wasthen heated at reflux for 90 minutes. An additional 35 mg of Zhan 1Bcatalyst was added and reaction mixture was heated at reflux for 45minutes. After cooling to room temperature, reaction mixture wasconcentrated in vacuo. The resulting residue was purified by silica gelchromatography (0-35% ethyl acetate in hexanes) to yield singlediastereomers 76-2 (early eluting component) as a white solid film and76-3 (late eluting component) as a brown solid film. Early eluting 76-2:LCMS-ESI (m/z): [M+H]⁺ calcd for C₃₅H₄₇F₂N₄O₇: 673.33. found: 673.45.Late eluting 76-3: LCMS-ESI (m/z): [M+H]⁺ calcd for C₃₅H₄₇F₂N₄O₇:673.33. found: 673.47.

Step 3. Preparation of 76-4: Palladium on carbon (10 wt % Pd, 51 mg,0.048 mmol) was added to a solution of 76-2 (175 mg, 0.260 mmol) in 9 mLof ethanol. The atmosphere was replaced with hydrogen and the reactionstirred overnight. The reaction mixture was filtered over Celite andwashed with ethanol. Filtrate was concentrated in vacuo to yield 76-4,which was used in the next step without further purification. LCMS-ESI⁺(m/z): [M+H]⁺ calcd for C₃₅H₄₉F₂N₄O₇: 675.35. found: 675.53.

Step 4. Preparation of 76-5: TFA (1.2 mL, 15.6 mmol) was added slowly toa solution of 76-4 (155 mg, 0.230 mmol) in 3.4 mL of dichloromethane.After 4 hours, mixture was concentrated under reduced pressure to neardryness. Resulting residue was taken up in 25 mL of ethyl acetate,washed with 15 mL of water, 15 mL of sat. NaHCO_(3 (aq)), and separated.Aqueous layers were extracted with ethyl acetate (3×20 mL). Combinedorganics were washed with 30 mL of brine, dried over anhydrous MgSO₄,filtered, and concentrated in vacuo to yield 76-5, which was used in thenext step without further purification. LCMS-ESI⁺ (m/z): [M+H]⁺ calcdfor C₃₁H₄₁F₂N₄O₇: 619.29. found: 619.44.

Step 5. Preparation of Example 76: HATU (160 mg, 0.421 mmol) and DIPEA(0.20 mL, 1.15 mmol) were added to a mixture of 76-5 (140 mg, 0.226mmol) and Intermediate A10 (139 mg, 0.457 mmol) in 7.5 mL of MeCN underargon. After stirring for overnight, reaction mixture was taken up in 30mL of ethyl acetate and washed with 20 mL of 1 N aqueous HCl. Layerswere separated and aqueous was extracted three times with ethyl acetate.Combined organics were washed with brine, dried over anhydrous MgSO₄,filtered, and concentrated in vacuo. The resulting residue was purifiedby silica gel chromatography (0-45% ethyl acetate in hexanes) andreverse phase prep HPLC (50-100% acetonitrile in water, with 0.1%trifluoroacetic acid buffer) to yield the trifluoroacetic acid salt ofExample 76 (. Analytic HPLC RetTime: 8.80 min. LCMS-ESI (m/z): [M+H]⁺calcd for C₄₀H₅₃F₄N₆O₉S: 869.35. found: 869.59. ¹H NMR (400 MHz, CD₃OD):9.19 (s, 1H), 7.94 (d, J=9.2 Hz, 1H), 7.32 (dd, J=9.2, 2.8 Hz, 1H), 7.27(d, J=2.8 Hz, 1H), 5.78 (td, J_(H-F)=56 Hz, J=7.2 Hz, 1H), 5.76-5.74 (m,1H), 4.56 (d, J=6.4 Hz, 1H), 4.48 (d, J=12 Hz, 1H), 4.27-4.19 (m, 1H),4.22 (s, 1H), 3.97 (s, 3H), 2.76-2.70 (m, 1H), 2.62-2.43 (m, 1H),2.14-1.94 (m, 3H), 1.90-1.80 (m, 1H), 1.80-1.62 (m, 3H), 1.56-1.52 (m,2H), 1.51 (s, 3H), 1.49 (s, 3H), 1.41-1.36 (m, 1H), 1.27-1.18 (m, 1H),1.11 (s, 9H), 1.09-1.04 (m, 5H), 1.03-0.94 (m, 2H), 0.87-0.81 (m, 3H),0.17-0.12 (m, 1H).

Example 77 Preparation of(1aS,5S,8S,9S,10R,22aS)-5-tert-butyl-N-[(1R,2R)-2-(difluoromethyl)-1-{[(1-methylcyclopropyl)sulfonyl]carbamoyl}cyclopropyl]-18,18-difluoro-14-methoxy-1a,9-dimethyl-3,6-dioxo-1,1a,3,4,5,6,9,10,18,19,20,21,22,22a-tetradecahydro-8H-7,10-methanocyclopropa[18,19][1,10,3,6]dioxadiazacyclononadecino[11,12-b]quinoxaline-8-carboxamide

Example 77 was prepared in a similar fashion to Example 76, substitutinglate eluting 76-3 for early eluting 76-2 in step 3. Example 76 was thenisolated. Analytic HPLC RetTime: 8.46 min. LCMS-ESI⁺ (m/z): [M+H]⁺ calcdfor C₄₀H₅₃F₄N₆O₉S: 869.35. found: 869.53. ¹H NMR (400 MHz, CD₃OD): 7.95(d, J=8.8 Hz, 1H), 7.32 (d, J=8.8 Hz, 1H), 7.28 (s, 1H), 6.58-6.54 (m,1H), 5.75 (td, J_(H-F)=55 Hz, J=6.8 Hz, 1H), 5.54-5.50 (m, 1H), 4.65 (d,J=6.8 Hz, 1H), 4.46 (d, J=12.8 Hz, 1H), 4.26-4.18 (m, 1H), 3.97 (s, 3H),2.92-2.71 (m, 1H), 2.50-1.94 (m, 6H), 1.68-1.57 (m, 2H), 1.56-1.52 (m,2H), 1.51 (s, 3H), 1.50-1.47 (m, 1H), 1.46-1.38 (m, 3H), 1.44 (s, 3H),1.27-1.18 (m, 2H), 1.17-1.01 (m, 3H), 1.09 (s, 9H), 0.94-0.82 (m, 4H),0.17-0.12 (m, 1H).

Example 78 Preparation of(1aR,5S,8S,9S,10R,19E,22aR)-5-tert-butyl-14-cyano-N-[(1R,2R)-2-(difluoromethyl)-1-{[(1-methylcyclopropyl)sulfonyl]carbamoyl}cyclopropyl]-9-ethyl-18,18-difluoro-3,6-dioxo-1,1a,3,4,5,6,9,10,17,17a,18,21,22,22a-tetradecahydro-8H-7,10-methanocyclopropa[18,19][1,10,3,6]dioxadiazacyclononadecino[11,12-b]quinoxaline-8-carboxamide

Steps 1-4. Intermediate 78-4 was prepared similarly to Intermediate17-4, using E6 in place of E3.

Step 5: To a solution of 78-4 (90 mg, 0.135 mmol) in EtOH (0.7 mL) wasadded NaBH₄ (21 mg, 0.54 mmol). The reaction mixture was stirred at rtfor 1 h. After which time the reaction mixture was filtered through apad of celite and concentrated to give intermediate 78-5, which was usedsubsequently without further purification. LCMS-ESI (m/z): [M+H]⁺ calcdfor C₃₅H₄₅F₂N₅O₆: 669.76. found: 669.73.

Steps 6 and 7: Preparation of Example 78: To a solution of 78-5 (35 mg,0.31 mmol) in DCM (0.4 mL), TFA (0.2 mL) was added and the mixture wasstirred at 20° C. for 3 h. Solvents were removed in vacuo to afford aresidue was used subsequently without further purification. To asuspension of this residue (33 mg, 0.05 mmol) and Intermediate A10 (27mg, 0.1 mmol) in DCM (0.3 mL) was added TBTU (26 mg, 0.08 mmol) andDIPEA (35 μL, 0.2 mmol) at rt. After 1 h, the solution was directlypurified by reverse phase HPLC (Gemini 5u C₁₈ ₁₁₀ Å column, 50-100%ACN/H₂O+0.1% TFA) and lyophilized to afford the TFA salt of Example 78.Analytical HPLC RetTime: 7.994 min. LCMS-ESI (m/z): [M+H]⁺ calcd forC₄₀H₄₉F₄N₇O₈S: 863.92. found: 864.20. ¹H NMR (400 MHz, CD3OD) δ 9.35 (s,1H), 7.29 (d, 1H), 7.18 (dd, 1H), 6.64 (d, 1H), 6.01-5.82 (m, 2H), 5.41(m, 2H), 4.57-4.07 (m, 5H), 3.52 (m, 1H), 2.55-2.28 (m, 2H), 2.06-1.98(m, 2H), 1.85 (m, 1H), 1.69-1.37 (m, 9H), 1.33 (m, 2H), 1.06-0.87 (m,16H), 0.70 (m, 2H)., 0.49 (m, 1H).

Example 79 Preparation of(1aS,2aR,6S,9S,10S,11R,23aR,23bS)-6-tert-butyl-15-chloro-N-[(1R,2R)-1-[(cyclopropylsulfonyl)carbamoyl]-2-(difluoromethyl)cyclopropyl]-10-methyl-4,7-dioxo-1a,2,2a,4,5,6,7,10,11,19,20,21,22,23,23a,23b-hexadecahydro-1H,9H-8,11-methanocyclopropa[4′,5′]cyclopenta[1′,2′:18,19][1,10,3,6]dioxadiazacyclononadecino[11,12-b]quinoxaline-9-carboxamide

Step 1. Preparation of 79-1. Sulfonyl quinoxaline E5 (920 mg, 3.32 mmol)was suspended in MeCN (17 mL), then treated with intermediate B1 (1.00g, 3.32 mmol) and Cs₂CO₃. After 17 h, the reaction mixture was filteredover celite and concentrated under reduced pressure. The crude residuewas purified by silica column chromatography (10% to 30% EtOAc/Hex) toafford ether 79-1. LCMS-ESI⁺ (m/z): [M-Boc+2H]⁺ calcd for O₁₈H₂₂Cl₂N₃O₃:398.10. found: 398.12.

Step 2. Preparation of 79-2. tert-Butyl carbamate 79-1 (513 mg, 1.03mmol) was dissolved in DCM (10 mL) and treated with HCl (4.0 mL indioxane, 5 mL, 20 mmol). The reaction mixture was stirred at RT for 1.5h, then concentrated under reduced pressure to afford aminehydrochloride 79-2, which was carried on without purification. LCMS-ESI(m/z): [M+H]⁺ calcd for C₁₈H₂₂Cl₂N₃O₃: 398.10. found: 398.16.

Step 3. Preparation of 79-3. Amine hydrochloride 79-2 (1.03 mmoltheoretical) and intermediate D12 (336 mg, 1.04 mmol) were combined andtreated with BEP (285 mg, 1.04 mmol), EtOAc (9 mL), NMP (1 mL) and DIPEA(0.90 mL, 5.2 mmol). The reaction mixture was stirred at 50° C. for 3 h,then cooled to RT. After an additional 15 h, the reaction mixture wasdiluted with EtOAc. The organic solution was washed with saturatedaqueous NaHCO₃ and brine, then dried over MgSO₄, filtered andconcentrated under reduced pressure. The crude residue was purified bysilica column chromatography (10% to 25% EtOAc/Hex) to afford amide79-3. LCMS-ESI (m/z): [M+H]⁺ calcd for C₃₆H₄₉Cl₂N₄O₆: 703.30. found:703.91.

Step 4. Preparation of 79-4. Chloro quinoxaline 79-3 (541 mg, 0.769mmol) was treated with potassium vinyltrifluoroborate (154 mg, 1.15mmol), Pd(dppf)Cl₂ dichloromethane adduct (63 mg, 0.077 mmol), EtOH (8mL) and triethylamine (0.16 mL, 1.15 mmol). The stirred mixture washeated to reflux for 1 h, then cooled to RT and diluted with EtOAc. Theorganic solution was washed with saturated aqueous NaHCO₃ and brine,then dried over MgSO₄, filtered and concentrated under reduced pressure.The crude residue was purified by silica column chromatography (10% to30% EtOAc/Hex) to afford vinyl quinoxaline 79-4. LCMS-ESI (m/z): [M+H]⁺calcd for C₃₈H₅₂ClN₄O₆: 695.36. found: 695.10.

Step 5. Preparation of 79-5. Vinyl quinoxaline 79-4 (390 mg, 0.561 mmol)was treated with DCE (112 mL) and Zhan-B catalyst (38 mg, 0.0561 mmol).The stirred mixture was degassed with bubbling N₂ for 25 min, thenheated to reflux under an Ar atmosphere. After 1.5 h, the mixture wascooled to RT and concentrated under reduced pressure. The crude residuewas purified by silica column chromatography (10% to 30% EtOAc/Hex) toafford macrocycle 79-5. LCMS-ESI (m/z): [M+H]⁺ calcd for C₃₆H₄₈ClN₄O₆:667.33. found: 667.86.

Step 6. Preparation of 79-6. Macrocycle 79-5 (198 mg, 0.297 mmol) wastreated with EtOAc (100 mL) and 5% Rh/alumina (100 mg). H₂ gas wasbubbled through the solution for 1 min and the reaction mixture wasstirred at RT under an atmosphere of H₂. After 45 min, more 5%Rh/alumina (200 mg) was added. Again, H₂ gas was bubbled through thesolution for 1 min and the reaction mixture was stirred at RT under anatmosphere of H₂. After another 1 h, the reaction mixture was filteredover celite and concentrated under reduced pressure. The material (79-6)was carried on without purification. LCMS-ESI (m/z): [M+H]⁺ calcd forC₃₆H₅₀ClN₄O₆: 669.34. found: 669.63.

Step 7. Preparation of 79-7. Macrocycle 79-6 (0.297 mmol theoretical)was treated with DCM (10 mL) and TFA (10 mL). The reaction mixture wasstirred at RT for 14 h, then concentrated under reduced pressure. Thecrude residue was dissolved in EtOAc and the organic solution was washedwith saturated aqueous NaHCO₃ and 1 M citric acid. Brine was added afterthe citric acid wash to break up the emulsion that formed. The organiclayer was dried over MgSO₄, filtered and concentrated under reducedpressure. The crude residue was purified by silica column chromatography(100% EtOAc) to afford impure 79-7 that was carried on without furtherpurification. LCMS-ESI (m/z): [M+H]⁺ calcd for C₃₂H₄₂ClN₄O₆: 613.28.found: 613.22.

Step 8. Preparation of Example 79. Carboxcylic acid 79-7 (0.264 mmoltheoretical) was treated with intermediate A9 (156 mg, 0.537 mmol), TBTU(170 mg, 0.528 mmol), DMAP (65 mg, 0.528 mmol), DCM (2 mL) and DIPEA(0.23 mL, 1.3 mmol). The reaction mixture was stirred at RT for 19 hthen concentrated under reduced pressure. The crude residue was purifiedby reverse phase HPLC to afford Example 79 as a TFA salt. LCMS-ESI(m/z): [M+H]⁺ calcd for C₄₀H₅₂ClF₂N₆O₈S: 849.32. found: 849.16. ¹H NMR(400 MHz, CD₃OD) δ 9.17 (s, 1H), 7.86 (t, J=8.1 Hz, 1H), 7.77 (t, J=3.5Hz, 1H), 7.55 (dd, J=8.8, 2.3 Hz, 1H), 5.84 (td, J=55.7, 6.7 Hz, 1H),5.62 (d, J=3.5 Hz, 1H), 4.98 (t, J=10.6 Hz, 1H), 4.53 (t, J=9.3 Hz, 1H),4.42-4.26 (m, 2H), 4.19 (dd, J=12.0, 3.9 Hz, 1H), 3.34 (d, J=7.6 Hz,1H), 2.99 (tt, J=8.2, 4.8 Hz, 2H), 2.78 (ddt, J=21.6, 14.2, 5.7 Hz, 2H),2.28-2.12 (m, 1H), 2.08-1.16 (m, 19H), 1.16-0.96 (m, 17H), 0.58 (dd,J=8.3, 4.1 Hz, 1H), 0.55-0.44 (m, 1H).

Example 80 Preparation of(3aR,7S,10S,11S,12R)-1-acetyl-7-tert-butyl-N-[(1R,2R)-2-(difluoromethyl)-1-{[(1-methylcyclopropyl)sulfonyl]carbamoyl}cyclopropyl]-16-methoxy-11-methyl-5,8-dioxo-1,2,3,3a,5,6,7,8,11,12,20,21,22,23,24,24a-hexadecahydro-1OH-9,12-methanopyrrolo[2′,3′:18,19][1,10,3,6]dioxadiazacyclononadecino[11,12-b]quinoxaline-10-carboxamide

Step 1. Preparation of 80-1: Amine 18-2 (195 mg, 0.495 mmol) andIntermediate D18 (192.8 mg, 0.544 mmol) were dissolved in DMF (10 mL).DIPEA (430 μL, 2.48 mmol) was added followed by HATU (207 mg, 0.544mmol) at room temperature. After 1.5 h, the reaction mixture wasconcentrated in vacuo and the crude residue was directly purified bysilica gel chromatography (0-100% ethyl acetate/hexanes gradient) toafford 80-1 (2:1 diastereomeric ratio favoring desired). LCMS-ESI (m/z):[M+H]⁺ calcd for C₃₇H₅₃ClN₅O₈: 730.3. found: 730.48.

Step 2. Preparation of 80-2: A stirred heterogeneous mixture of 80-1(314 mg, 0.431 mmol), PdCl₂(dppf)*CH₂Cl₂ (35.2 mg, 0.043 mmol) andpotassium vinyltrifluoroborate (86.6 mg, 0.646 mmol) in EtOH (2.2 mL)was sparged with argon for 15 min. Triethylamine (320 μL, 2.3 mmol) wasadded and the mixture was heated to 80° C. After 40 min, the reactionmixture was cooled to ambient temperature and was diluted with toluene(5 mL). The resulting mixture was concentrated and the crude residue wasdirectly purified by silica gel chromatography (0-100% ethylacetate/hexanes gradient) to afford 80-2 (2:1 diastereomeric ratiofavoring desired). LCMS-ESI (m/z): [M+H]⁺ calcd for C₃₉H₅₆N₅O₈: 722.4.found: 722.54.

Step 3. Preparation of 80-3: 80-2 (228 mg, 0.320 mmol) was dissolved inDCE (64 mL) and the solution was sparged with Ar for 15 min. Zhan 1Bcatalyst (23 mg, 0.032 mmol) was added and the resulting solution wasstirred at 100° C. under Ar. After 45 min, the reaction mixture wascooled to rt, was concentrated in vacuo and was directly purified bysilica gel chromatography (0-100% ethyl acetate/hexanes gradient) toafford 80-3 (5:2 diastereomeric ratio favoring desired). LCMS-ESI (m/z):[M+H]⁺ calcd for C₃₇H₅₂N₅O₈: 694.37. found: 694.53.

Step 4: Preparation of 80-4: Olefin 80-3 (164 mg, 0.237 mmol) wasdissolved in ethanol (1.19 mL) and the reaction vessel was purged withAr. Pd/C (10 wt % Pd, 25 mg) was added in a single portion and thereaction vessel was purged thrice with H₂. The reaction was stirred atrt under 1 atm H₂ for 2 h and was diluted with ethyl acetate (10 mL).The resulting mixture was filtered through a pad of Celite andconcentrated to afford a crude residue of 80-4 (5:2 diastereomeric ratiofavoring desired) that was used without further purification (LCMS-ESI(m/z): [M+H]⁺ calcd for C₃₇H₅₄N₅O₈: 696.39. found: 696.56.

Step 5. Preparation of 80-5: To a solution of 80-4 (164 mg, 240 μmol) inDCM (1.2 mL) was added TFA (0.45 mL) at rt. After 7 h, the reactionmixture was diluted with ethyl acetate (50 mL) and the resulting mixturewas extracted with 1N aqueous sodium hydroxide solution (40 mL). Theaqueous layer was then slowly acidified to pH=3 with concentratedhydrochloric acid, and was extracted with ethyl acetate (2×50 mL). Thecombined organic extracts were dried over anhydrous sodium sulfate andwere concentrated in vacuo. The residue was azeotropically dried withtoluene (3×5 mL) to afford 80-5 (5:2 diastereomeric ratio favoringdesired) that was used without further purification. LCMS-ESI (m/z):[M+H]⁺ calcd for C₃₃H₄₆N₅O₈: 640.33. found: 640.48.

Step 6. Preparation of Example 80: To a solution of 80-5 (140 mg, 219μmol) and Intermediate A10 (133 mg, 438 μmol) in MeCN (1.1 mL) was addedHATU (169 mg, 438 μmol) followed by DIPEA (190 μL, 1.09 mmol) at rtunder an argon atmosphere. After 15 h, the reaction mixture wasconcentrated in vacuo, was purified by preparatory HPLC (Gemini 5u C18110 Å column, 5-100% MeCN/H₂O, 0.1% trifluoroacetic acid modifier) andwas lyophilized to afford Example 80 (5:2 diastereomeric ratio favoringdesired) as a light yellow solid TFA salt. Analytic HPLC RetTime: 7.91min. LCMS-ESI (m/z): [M+H]⁺ calcd for C₄₂H₅₈F₂N₇O₁₀S: 890.39. found:890.64. ¹H NMR (400 MHz, CD₃OD, Minor diastereomer denoted by *) δ 9.18(s, 1H), 9.14 (s, 1H*), 7.78 (br d, J=9.0 Hz, 1H, 1H*), 7.21 (br d,J=9.0 Hz, 1H, 1H*), 7.18 (br s, 1H, 1H*), 5.80 (br td, J_(H-F)=55.8 Hz,J=6.8 Hz, 1H, 1H*), 5.64 (br s, 1H, 1H*), 5.23 (d, J=4.7 Hz, 1H*), 5.15(d, J=4.7 Hz, 1H), 4.56 (d, J=6.7 Hz, 1H, 1H*), 4.46 (d, J=12.1 Hz,1H*), 4.41 (d, J=12.0 Hz, 1H), 4.30-4.22 (m, 1H, 1H*), 4.22-4.07 (m, 1H,1H*), 4.02-3.79 (m, 1H, 1H*) 3.92 (br s, 3H, 3H*), 3.73-3.52 (m, 2H,2H*), 3.05-2.68 (m, 3H, 3H*), 2.40-2.21 (m, 1H, 1H*), 2.13-1.94 (m, 4H,4H*), 1.83 (s, 2H, 2H*), 1.75-1.20 (m, 12H, 12H*), 1.12 (s, 9H*),1.10(s, 9H), 1.06 (br d, J=7.3 Hz, 3H, 3H*), 0.92-0.85 (m, 4H, 4H*).

Example 81 Preparation of(1aS,2aR,6S,9S,10S,11R,23aR,23bS)-6-tert-butyl-N-[(1R,2R)-2-(difluoromethyl)-1-{[(1-methylcyclopropyl)sulfonyl]carbamoyl}cyclopropyl]-19,19-difluoro-15-methoxy-10-methyl-4,7-dioxo-1a,2,2a,4,5,6,7,10,11,19,20,21,22,23,23a,23b-hexadecahydro-1H,9H-8,11-methanocyclopropa[4′,5′]cyclopenta[1′,2′:18,19][1,10,3,6]dioxadiazacyclononadecino[11,12-b]quinoxaline-9-carboxamide

Example 81 was prepared in a similar fashion to Example 62, substitutingIntermediate A10 for Intermediate A9 in Step 5. Example 81 was isolated.Analytic HPLC RetTime: 9.36 min. LCMS-ESI⁺ (m/z): [M+H]⁺ calcd forC₄₂H₅₅F₄N₆O₉S: 895.36. found: 895.59. ¹H NMR (400 MHz, CD₃OD): δ 9.23(s, 1H), 7.93 (d, J=8.8 Hz, 1H), 7.31 (dd, J=8.8, 2.4 Hz, 1H), 7.26 (d,J=2.4 Hz, 1H), 5.80 (td, J_(H-F)=56 Hz, J=6.8 Hz, 1H), 5.73 (d, J=3.2Hz, 1H), 4.94 (d, J=7.2 Hz, 1H), 4.56 (d, J=6.8 Hz, 1H), 4.36 (d, J=6.8Hz, 1H), 4.32 (s, 1H), 4.22-4.16 (dd, J=12, 4 Hz, 1H), 3.97 (s, 3H),2.79-2.71 (m, 1H), 2.61-2.52 (m, 1H), 2.26-2.16 (m, 1H), 2.08-1.92 (m,4H), 1.82-1.64 (m, 3H), 1.60-1.54 (m, 3H), 1.53-1.46 (m, 1H), 1.52 (s,3H), 1.44-1.26 (m, 5H), 1.08 (s, 9H), 1.07-0.98 (m, 4H), 0.94-0.84 (m,3H), 0.60-0.48 (m, 2H).

Example 82 Preparation of(1aS,2aR,6S,9S,10S,11R,23aR,23bS)-6-tert-butyl-N-[(1R,2R)-2-(difluoromethyl)-1-{[(1-methylcyclopropyl)sulfonyl]carbamoyl}cyclopropyl]-19,19-difluoro-10-methyl-4,7-dioxo-1a,2,2a,4,5,6,7,10,11,19,20,21,22,23,23a,23b-hexadecahydro-1H,9H-8,11-methanocyclopropa[4′,5′]cyclopenta[1′,2′:18,19][1,10,3,6]dioxadiazacyclononadecino[11,12-b]quinoxaline-9-carboxamide

Intermediate 82-1 was prepared in a similar fashion to intermediate46-2, substituting intermediate E3 with E4 in Step 1. LCMS-ESI⁺ (m/z):[M+H]⁺ calcd for C₂₆H₃₄F₂N₃O₅: 506.25. found: 506.59.

Example 82 was prepared in a similar fashion to Example 62, substitutingIntermediate 82-1 for Intermediate 46-2 in Step 1. Example 82 wasisolated. LCMS-ESI⁺ (m/z): [M+H]⁺ calcd for C₄₁H₅₂F₄N₆O₈S: 864.35.found: 865.43. ¹H NMR (400 MHz, cdcl₃) δ 9.82 (s, 1H), 7.89-7.72 (m,2H), 7.67 (t, J=7.6 Hz, 1H), 6.93 (s, 1H), 6.12-5.65 (m, 2H), 5.34 (d,J=8.6 Hz, 1H), 4.90 (d, J=7.4 Hz, 1H), 4.45 (t, J=9.3 Hz, 2H), 4.27 (d,J=7.9 Hz, 1H), 4.13 (dd, J=11.9, 3.9 Hz, 1H), 2.77-2.64 (m, 2H),2.27-2.12 (m, 1H), 2.13-1.86 (m, 4H), 1.82-1.19 (m, 15H), 1.18-0.98 (m,13H), 0.89-0.77 (m, 2H), 0.53 (dd, J=13.3, 8.1 Hz, 1H), 0.43 (d, J=4.2Hz, 1H).

Example 83 Preparation of(1aR,5S,8S,9S,10R,22aR)-5-tert-butyl-N-[(1R,2R)-2-(difluoromethyl)-1-{[(1-methylcyclopropyl)sulfonyl]carbamoyl}cyclopropyl]-9-ethyl-18,18-difluoro-3,6-dioxo-14-(trifluoromethoxy)-1,1a,3,4,5,6,9,10,18,19,20,21,22,22a-tetradecahydro-8H-7,10-methanocyclopropa[18,19][1,10,3,6]dioxadiazacyclononadecino[11,12-b]quinoxaline-8-carboxamide

Step 1. Preparation of 83-1: HATU (3.06 g, 8.05 mmol) was added slowlyto a solution of 3,3-difluoro-2-oxopent-4-enoic acid (1.03 g, 6.86 mmol)in 10 mL of DMF. A mixture of 4-(trifluoromethoxy)benzene-1,2-diamine(1.29 g, 6.71 mmol) and DIPEA (1.4 mL, 8.05 mmol) in 12 mL of DMF wasthen added. After stirring overnight, reaction mixture was poured into175 mL of water and extracted with ethyl acetate (4×100 mL). Combinedorganics were washed with 50% brine, dried over anhydrous Na₂SO₄,filtered, and concentrated under reduced pressure. Resulting solid waspurified via silica gel column chromatography (0-25% ethyl acetate inhexanes) to yield intermediate 83-1, the late eluting product. LCMS-ESI(m/z): [M+H]⁺ calcd for C₁₂H₈F₅N₂O₂: 307.04. found: 307.29.

Step 2. Preparation of 83-2: A solution of 83-1 (924 mg, 3.01 mmol) in 2mL DMF was treated with POCl₃ (0.56 mL, 6.04 mmol) and heated at 80° C.for 2.5 hours. After cooling to room temperature, reaction mixture wasdiluted with 25 mL of EtOAc and added slowly to 20 mL of water withvigorous stirring. Layers were separated and aqueous was extracted withethyl acetate. Combined organics were washed subsequently with saturatedaqueous sodium bicarbonate and brine, dried over anhydrous sodiumsulfate and concentrated under reduced pressure to give intermediate83-2. LCMS-ESI (m/z): [M+H]⁺ calcd for C₁₂H₇ClF₅N₂O: 324.01. found:324.13.

Step 3. Preparation of 83-3: Cs₂CO₃ (606 mg, 1.86 mmol) was added to amixture of intermediate 83-2 (460 mg, 1.54 mmol) and intermediate B4(564 mg, 1.79 mmol) in 12 mL of DMF at room temperature. Reactionmixture was heated at 85° C. overnight. After cooling to roomtemperature, mixture was poured into 50 mL of water and extracted withethyl acetate (4×40 mL). Combined organics were washed with 90 mL of 50%brine, dried over anhydrous sodium sulfate and concentrated underreduced pressure. Resulting solid was purified via silica gel columnchromatography (0-30% ethyl acetate in hexanes) to give 83-3. LCMS-ESI(m/z): [M+H]⁺ calcd for C₂₈H₃₅F₅N₃O₆: 604.24. found: 604.20.

Step 4. Preparation of 83-4: Quinoxaline ether 83-3 (290 mg, 0.647 mmol)was dissolved in 4.1 mL of tert-butyl acetate and 1.1 mL ofdichloromethane at room temperature. MeSO₃H (0.25 mL, 3.88 mmol) wasadded dropwise and reaction mixture stirred at rt for 2 h. The reactionmixture was transferred to a stirred mixture of EtOAc (20 mL) andsaturated aqueous NaHCO₃ (30 mL). The phases were separated, and theaqueous phase was extracted with EtOAc (2×20 mL). The combined organicphase was dried over anhydrous Na₂SO₄, filtered, and concentrated invacuo to afford amine 83-4. LCMS-ESI (m/z): [M+H]⁺ calcd forC₂₃H₂₇F₅N₃O₄: 504.18. found: 504.31.

Step 5. Preparation of 83-5: HATU (260 mg, 0.684 mmol, Oakwood) andDIPEA (0.40 mL, 2.30 mmol) were added to a mixture of 83-4 (258 mg,0.512 mmol) and Intermediate D11 (177 mg, 0.657 mmol) in 7 mL ofacetonitrile under argon. After stirring overnight, the reaction mixturewas concentrated under reduced pressure and the resulting residue waspurified by silica gel chromatography (0-20% ethyl acetate in hexanes)to yield 83-5. LCMS-ESI (m/z): [M+H]⁺ calcd for C₃₇H₄₈F₅N₄O₇: 755.34.found: 755.49.

Step 6. Preparation of 83-6: A mixture of 83-5 (215 mg, 0.285 mmol) andZhan 1B catalyst (29 mg, 0.040 mmol, Strem) in 60 mL of DCE wasdeoxygenated with argon for 15 minutes. The mixture was then heated atreflux for 90 minutes. After cooling to room temperature, reactionmixture was concentrated in vacuo. The resulting residue was purified bysilica gel chromatography (0-40% ethyl acetate in hexanes) to yield83-6. LCMS-ESI (m/z): [M+H]⁺ calcd for C₃₅H₄₄F₅N₄O₇: 727.31. found:727.43.

Step 7. Preparation of 83-7: Palladium on carbon (10 wt % Pd, 40 mg,0.038 mmol) was added to a solution of 83-6 (129 mg, 0.178 mmol) in 9 mLof ethanol. The atmosphere was replaced with hydrogen and the reactionstirred overnight. The reaction mixture was filtered over Celite andwashed with ethanol. Filtrate was concentrated in vacuo to yield aresidue, which was purified via silica gel column chromatography (0-30%ethyl acetate in hexanes) to yield 83-7. LCMS-ESI (m/z): [M+H]⁺ calcdfor C₃₅H₄₆F₅N₄O₇: 729.32. found: 729.45.

Step 8. Preparation of 83-8: TFA (0.62 mL, 8.09 mmol) was added slowlyto a solution of 83-7 (79 mg, 0.109 mmol) in 1.8 mL of dichloromethane.After 4 hours, mixture was concentrated under reduced pressure to neardryness. Resulting residue was taken up in 10 mL of ethyl acetate,washed with 8 mL of water, 8 mL of sat. NaHCO_(3 (aq)), and separated.Aqueous layers were extracted with ethyl acetate (3×10 mL). Combinedorganics were washed with 10 mL of brine, dried over anhydrous Na₂SO₄,filtered, and concentrated in vacuo to yield 83-8, which was used in thenext step without further purification. LCMS-ESI (m/z): [M+H]⁺ calcd forC₃₁H₃₈F₅N₄O₇: 673.26. found: 673.10.

Step 9. Preparation of Example 83: HATU (84 mg, 0.221 mmol, Oakwood) andDIPEA (0.095 mL, 0.547 mmol) were added to a mixture of 83-8 (72 mg,0.107 mmol) and Intermediate A10 (66 mg, 0.217 mmol) in 4 mL ofacetonitrile under argon. After stirring for overnight, reaction mixturewas taken up in 20 mL of ethyl acetate and washed with 10 mL of 1 Naqueous HCl. The aqueous layer was extracted three times with ethylacetate. Combined organics were washed with 50% brine, dried overanhydrous Na₂SO₄, filtered, and concentrated in vacuo. The resultingresidue was purified by silica gel chromatography (0-50% ethyl acetatein hexanes) and reverse phase prep HPLC (50-100% acetonitrile in water,with 0.1% trifluoroacetic acid buffer) to yield the trifluoroacetic acidsalt of Example 83. Analytic HPLC RetTime: 9.12 min. LCMS-ESI⁺ (m/z):[M+H]⁺ calcd for C₄₀H₅₀F₇N₆O₉S: 923.32. found: 923.10. ¹H NMR (400 MHz,CD₃OD): δ 9.26 (s, 1H), 8.01-7.91 (m, 2H), 7.78-7.63 (m, 1H), 5.95 (d,J=3.6 Hz, 1H), 5.83 (td, J_(H-F)=61 Hz, J=6.0 Hz, 1H), 4.59 (d, J=7.2Hz, 1H), 4.42 (d, J=12.4 Hz, 1H), 4.35 (s, 1H), 4.22-4.11 (m, 1H),3.72-3.66 (m, 1H), 2.71-2.49 (m, 2H), 2.18-1.94 (m, 3H), 1.90-1.75 (m,3H), 1.74-1.62 (m, 2H), 1.60-1.48 (m, 3H), 1.51 (s, 3H), 1.50-1.24 (m,4H), 1.22-1.18 (m, 2H), 1.08 (s, 9H), 1.07-0.84 (m, 5H), 0.81-0.64 (m,1H), 0.54-0.44 (m, 1H).

Example 84 Preparation of(1aR,5S,8S,9S,10R,19E,22aR)-5-tert-butyl-14-cyano-N-[(1R,2R)-2-(difluoromethyl)-1-{[(1-methylcyclopropyl)sulfonyl]carbamoyl}cyclopropyl]-9-ethyl-18,18-difluoro-3,6-dioxo-1,1a,3,4,5,6,9,10,18,21,22,22a-dodecahydro-8H-7,10-methanocyclopropa[18,19][1,10,3,6]dioxadiazacyclononadecino[11,12-b]quinoxaline-8-carboxamide

Step 1: Preparation of Example 84. Crude Example 78 (8.7 mg, 0.01 mmol)was redissolved in ACN (0.3 mL) and treated with DDQ (3.4 mg, 0.015mmol). After 10 min, the solution was directly purified by reverse phaseHPLC (Gemini 5u C18 110 Å column, 50-100% ACN/H₂O+0.1% TFA) andlyophilized to afford the TFA salt of Example 84. Analytical HPLCRetTime: 8.385 min. LCMS-ESI⁺ (m/z): [M+H]⁺ calcd for C₄₀H₄₇F₄N₇O₈S:861.90. found: 862.89. ¹H NMR (400 MHz, CD3OD)¹H NMR (400 MHz, CD3OD) δ9.21 (s, 1H), 8.25 (d, 1H), 8.20 (d, 1H), 0.7.91 (dd, 1H), 6.32 (m, 2H),5.97-5.61 (m, 2H), 4.82 (m, 1H), 4.58-4.13 (m, 4H), 3.71-3.49 (m, 3H),2.61 (m, 2H), 2.23 (m, 1H), 2.00-1.80 (m, 3H), 1.56-1.20 (m, 10H), 1.20(m, 3H), 1.07 (m, 8H), 0.98-0.82 (m, 3H)., 0.55 (m, 1H).

Example 85 Preparation of(1aR,5S,8S,9S,10R,22aR)-5-tert-butyl-14-(difluoromethoxy)-N-[(1R,2R)-2-(difluoromethyl)-1-{[(1-methylcyclopropyl)sulfonyl]carbamoyl}cyclopropyl]-9-ethyl-18,18-difluoro-3,6-dioxo-1,1a,3,4,5,6,9,10,18,19,20,21,22,22a-tetradecahydro-8H-7,10-methanocyclopropa[18,19][1,10,3,6]dioxadiazacyclononadecino[11,12-b]quinoxaline-8-carboxamide

Example 85 was prepared similarly to Example 83, by using intermediateE7 in place of 83-2 in step 3. Analytical HPLC RetTime: 8.725 min.LCMS-ESI (m/z): [M+H]⁺ calcd for C₄₀H₅₀F₆N₆O₉S: 904.92. found: 905.16.¹H NMR (400 MHz, CD3OD) δ 9.23 (s, 1H), 7.88 (d, 1H), 7.76 (d, 1H),0.7.62 (dd, 1H), 7.03 (dd, 1H), 5.94-5.65 (m, 3H), 4.57-4.14 (m, 4H),3.66 (m, 1H), 2.57 (m, 2H), 2.01-1.97 (m, 3H), 1.82-1.77 (m, 3H), 1.64(m, 1H), 1.57-1.33 (m, 10H), 1.20 (m, 3H), 1.06-0.87 (m, 12H), 0.87 (m,2H)., 0.48 (m, 1H).

Example 86 Preparation of(1aS,2aR,6S,9S,10S,11R,23aR,23bS)-6-tert-butyl-N-[(1R,2R)-2-(difluoromethyl)-1-{[(1-methylcyclopropyl)sulfonyl]carbamoyl}cyclopropyl]-15-fluoro-10-methyl-4,7-dioxo-1a,2,2a,4,5,6,7,10,11,19,20,21,22,23,23a,23b-hexadecahydro-1H,9H-8,11-methanocyclopropa[4′,5′]cyclopenta[1′,2′:18,19][1,10,3,6]dioxadiazacyclononadecino[11,12-b]quinoxaline-9-carboxamide

Step 1. Preparation of 86-1: To a solution of E8 (1.5 g, 5.75 mmol) andB1 (1.9 g, 6.34 mmol) in MeCN (50 mL) is added Cs₂CO₃ (3.09 g, 9.49mmol). After stirring at rt for 60 h, the reaction mixture was filteredover celite and concentrated. The crude residue was purified by silicagel chromatography (5-35% EtOAc/hexanes) to yield product 86-1.LCMS-ESI⁺ (m/z): [M+H]⁺ calcd for C₂₃H₃₀ClFN₃O₅— Boc: 482.13. found:382.04.

Step 2. Preparation of 86-2: To a solution of 86-1 (747 mg, 1.55 mmol)in CH₂Cl₂ (5 mL) is added HCl (5 mL, 4 M in dioxane) and allowed to stirfor 3 h. The reaction mixture was concentrated to give a residue thatwas used subsequently without further purification. LCMS-ESI⁺ (m/z):[M+H]⁺ calcd for C₁₈H₂₃Cl₂FN₃O₃—HCl: 382.13. found: 382.08.

Step 3. Preparation of 86-3: To a solution of 86-2 (397 mg, 0.95 mmol),D12 (308 mg, 0.95 mmol) and BEP (312 mg, 1.14 mmol) in EtOAc (9 mL) andNMP (1 mL) was added DIPEA (0.7 mL, 3.8 mmol) and the reaction wasstirred at 50° C. overnight. The reaction was quenched with sat. NaHCO₃solution and extracted with EtOAc, washed subsequently with brine, driedover magnesium sulfate and concentrated. The crude product was purifiedby silica gel to yield 86-3. LCMS-ESI⁺ (m/z): [M+H]⁺ calcd forC₃₆H₄₉ClFN₄O₆: 687.33. found: 687.44.

Step 4. Preparation of 86-4: To a solution of 86-3 (266 mg, 0.39 mmol),TEA (0.08 mL, 0.58 mmol) and potassium vinyltrifluoroborate (78 mg, 0.58mmol) in EtOH (8 mL) was added PdCl₂(dppf) (32 mg, 0.04 mmol). Thereaction was degassed with N₂ for 10 min and heated to 75° C. for 1 h.The reaction was quenched with sat. NaHCO₃ solution and extracted withEtOAc, washed subsequently with brine, dried over magnesium sulfate andconcentrated. The residue was purified using silica gel chromatography(0-25% EtOAc/hexanes) to give 86-4. LCMS-ESI (m/z): [M+H]⁺ calcd forC₃₈H₅₂FN₄O₆: 679.39. found: 679.52.

Step 5 and 6. Preparation of 86-5: To a solution of 86-4 (262 mg, 0.38mmol) in DCE (50 mL) was added Zhan 1B catalyst (28 mg, 0.04 mmol) andthe reaction was degassed for 25 minutes with N₂. The reaction washeated to 100° C. for 1 h, allowed to cool to rt and concentrated. Thecrude product was purified by silica gel chromatography (0-30%EtOAc/hexanes) to give olefin product (182 mg; LCMS-ESI (m/z): [M+H]⁺calcd for C₃₆H₄₈FN₄O₆: 651.36. found: 651.38) that was taken up in EtOH(5 mL) and EtOAc (1 mL) and treated with Pd/C (10%, 55 mg). Theatmosphere was replaced with hydrogen and stirred at rt for 1.25 h. Thereaction was filtered over Celite, washed with EtOAc and concentrated togive 86-5 that was used subsequently without further purification.LCMS-ESI⁺ (m/z): [M+H]⁺ calcd for C₃₆H₅₀FN₄O₆: 653.37. found: 653.46.

Step 7. Preparation of 86-6: To a solution of 86-5 (182 mg, 0.28 mmol)in DCM (3 mL) was added TFA (3 mL) and stirred at rt for 18 h. Thereaction was diluted with EtOAc, washed with H₂O, basicified to pH 7with sat. NaHCO₃ solution, washed with 1M citric acid solution, driedover magnesium sulfate, and concentrated to give a residue of 86-6 thatwas used subsequently without further purification. LCMS-ESI (m/z):[M+H]⁺ calcd for C₃₂H₄₂FN₄O₆: 597.31. found: 597.15.

Step 8. Preparation of Example 86: To a solution of 86-6 (24 mg, 0.04mmol), intermediate A10 (18 mg, 0.06 mmol), TBTU (23 mg, 0.07 mmol) andDMAP (7 mg, 0.06 mmol) in DMF (3 mL) was added DIPEA (35 μL, 0.20 mmol)and the reaction was stirred at rt for 3 h. Additional intermediate A10(18 mg, 0.06 mmol), TBTU (23 mg, 0.07 mmol), DMAP (7 mg, 0.06 mmol), andDIPEA (35 μL, 0.20 mmol) was added and the reaction was stirred at rtfor 16 h. The crude material was purified by reverse phase HPLC (Gemini,30-85% ACN/H₂O+0.1% TFA) and lyophilized to give Example 86 as a TFAsalt. Analytical HPLC RetTime: 9.25 min. LCMS-ESI⁺ (m/z): [M+H]⁺ calcdfor C₄₁H₅₄F₃N₆O₈S: 847.37; found: 847.18. ¹H NMR (400 MHz, CD₃OD) δ 9.18(s, 1H), 8.13-7.84 (m, 2H), 7.59-7.21 (m, 2H), 6.07-5.58 (m, 2H), 5.00(d, J=7.4 Hz, 1H), 4.57 (d, J=7.0 Hz, 1H), 4.45-4.27 (m, 2H), 4.20 (dd,J=12.0, 4.0 Hz, 1H), 3.11-2.94 (m, 3H), 2.92-2.70 (m, 4H), 2.32-2.14 (m,1H), 2.10-1.94 (m, 2H), 1.86 (m, 1H), 1.77 (d, J=14.5 Hz, 1H), 1.74-1.21(m, 15H), 1.21-1.01 (m, 10H), 1.00-0.84 (m, 2H), 0.60 (m, 1H), 0.53 (m,1H).

Example 87 Preparation of(1aR,5S,8S,9S,10R,22aR)-5-tert-butyl-14-cyano-N-[(1R,2R)-2-(difluoromethyl)-1-{[(1-methylcyclopropyl)sulfonyl]carbamoyl}cyclopropyl]-9-ethyl-18,18-difluoro-3,6-dioxo-1,1a,3,4,5,6,9,10,18,19,20,21,22,22a-tetradecahydro-8H-7,10-methanocyclopropa[18,19][1,10,3,6]dioxadiazacyclononadecino[11,12-b]quinoxaline-8-carboxamide

Steps 1 and 2. Preparation of Example 87. To a solution of Example 84(100 mg, 0.11 mmol) in EtOAc (3 mL) was added Pd/C (10 wt % Pd, 30 mg).The reaction vessel was purged twice with H₂ and was stirred at rt under1 atm H₂ for 6 h. After which time the reaction mixture was filteredthrough a pad of celite and concentrated. The reaction reduced thequinoxaline ring. The crude material was redissolved in ACN (5 mL) andtreated with DDQ (34 mg, 0.15 mmol). After 1 h, the solution wasdirectly purified by reverse phase HPLC (Gemini 5u C18 110 Å column,50-100% ACN/H₂O+0.1% TFA) and lyophilized to afford the TFA salt ofExample 87. Analytical HPLC RetTime: 8.463 min. LCMS-ESI⁺ (m/z):[M+H]⁺calcd for C₄₀H₄₉F₄N₇O₈S: 863.92. found: 864.18. ¹H NMR (400 MHz,CD3OD) δ 9.24 (s, 1H), 8.27 (d, 1H), 8.20 (d, 1H), 0.7.91 (dd, 1H),5.93-5.82 (m, 3H), 4.88 (m, 1H), 4.58-4.13 (m, 5H), 3.71-3.49 (m, 3H),2.59 (m, 2H), 2.03-1.96 (m, 3H), 1.82-1.77 (m, 3H), 1.65-1.35 (m, 11H),1.20 (m, 3H), 1.06-0.87 (m, 8H), 0.71 (m, 2H)., 0.48 (m, 1H).

Example 88 Preparation of(1aR,5S,8S,9S,10R,22aR)-5-tert-butyl-14-chloro-N-[(1R,2R)-2-(difluoromethyl)-1-{[(1-methylcyclopropyl)sulfonyl]carbamoyl}cyclopropyl]-18,18-difluoro-9-methyl-3,6-dioxo-1,1a,3,4,5,6,9,10,18,19,20,21,22,22a-tetradecahydro-8H-7,10-methanocyclopropa[18,19][1,10,3,6]dioxadiazacyclononadecino[11,12-b]quinoxaline-8-carboxamide

Step 1. Preparation of 88-1: HATU (4.56 g, 12 mmol) was added slowly toa solution of 3,3-difluoro-2-oxopent-4-enoic acid (1.52 g, 10.1 mmol) in14 mL of DMF. A mixture of 4-chlorobenzene-1,2-diamine (1.43 g, 10 mmol)and DIPEA (2.1 mL, 12 mmol) in 20 mL of DMF was then added. Afterstirring overnight, reaction mixture was poured into 30 mL of 1 Naqueous HCl and extracted with ethyl acetate (5×40 mL). Combinedorganics were dried over anhydrous Na₂SO₄, filtered, and concentratedunder reduced pressure. Resulting solid was purified via silica gelcolumn chromatography (0-45% ethyl acetate in hexanes) to yieldintermediate 88-1 as the late eluting product. ¹H NMR (400 MHz, CDCl₃):δ 12.1 (s, 1H), 7.99 (m, 1H), 7.61-7.58 (m, 1H), 7.33-7.31 (m, 1H),6.61-6.48 (m, 1H), 5.96-5.90 (m, 1H), 5.67-5.63 (m, 1H).

Step 2. Preparation of 88-2: A solution of intermediate 88-1 (648 mg,2.53 mmol) in 2 mL DMF was treated with POCl₃ (0.49 mL, 5.26 mmol) andheated at 80° C. for 3 hours. After cooling to room temperature,reaction mixture was diluted with 20 mL of EtOAc and added slowly to 15mL of water with vigorous stirring. Layers were separated and aqueouswas extracted with ethyl acetate. Combined organics were washedsubsequently with saturated aqueous sodium bicarbonate and brine, driedover anhydrous sodium sulfate and concentrated under reduced pressure togive intermediate 88-2. ¹H NMR (400 MHz, CDCl₃) b 8.184 (d, J=1.6 Hz,1H), 8.01 (d, J=8.8 Hz, 1H), 7.82 (dd, J=9.4, 2 Hz, 1H), 6.56-6.43 (m,1H), 5.88 (m, 1H), 5.70 (d, J=10.8 Hz, 1H).

Step 3. Preparation of 88-3: Cs₂CO₃ (660 mg, 2.03 mmol) was added to amixture of intermediate 88-2 (425 mg, 1.54 mmol) and intermediate B1(570 mg, 1.89 mmol) in 9 mL of DMF at room temperature. Reaction mixturewas heated at 85° C. overnight. After cooling to room temperature,mixture was poured into 40 mL of water and extracted with ethyl acetate(4×30 mL). Combined organics were washed with 75 mL of 50% brine, driedover anhydrous sodium sulfate and concentrated under reduced pressure.Resulting solid was purified via silica gel column chromatography (0-20%ethyl acetate in hexanes) to give 88-3. LCMS-ESI (m/z): [M+H]⁺ calcd forC₂₆H₃₃ClF₂N₃O₅: 540.20. found: 540.12.

Step 4. Preparation of 88-4: Quinoxaline ether 88-3 (458 mg, 0.848 mmol)was dissolved in 4.2 mL of tert-butyl acetate and 1.2 mL ofdichloromethane at room temperature. MeSO₃H (0.30 mL, 4.67 mmol) wasadded dropwise and reaction mixture stirred at rt for 2 h. The reactionmixture was transferred to a stirred mixture of EtOAc (20 mL) andsaturated aqueous NaHCO₃ (30 mL). The phases were separated, and theaqueous phase was extracted with EtOAc (2×20 mL). The combined organicphase was dried over anhydrous Na₂SO₄, filtered, and concentrated invacuo to afford amine 88-4 as a yellow solid film LCMS-ESI (m/z): [M+H]⁺calcd for C₂₁H₂₅ClF₂N₃O₃: 440.15. found: 440.29.

Step 5. Preparation of 88-5: HATU (360 mg, 0.947 mmol, Oakwood) andDIPEA (0.51 mL, 2.91 mmol) were added to a mixture of 88-4 (320 mg,0.727 mmol) and Intermediate D11 (237 mg, 0.880 mmol) in 10 mL ofacetonitrile under argon. After stirring overnight, the reaction mixturewas concentrated under reduced pressure and the resulting residue waspurified by silica gel chromatography (0-20% ethyl acetate in hexanes)to yield 88-5. LCMS-ESI (m/z): [M+H]⁺ calcd for C₃₅H₄₆ClF₂N₄O₆: 691.30.found: 691.50.

Step 6. Preparation of 88-6: A mixture of 88-5 (390 mg, 0.564 mmol) andZhan 1B catalyst (55 mg, 0.075 mmol, Strem) in 100 mL of DCE wasdeoxygenated with argon for 15 minutes. The mixture was then heated atreflux for 110 minutes. After cooling to room temperature, reactionmixture was concentrated in vacuo. The resulting residue was purified bysilica gel chromatography (0-25% ethyl acetate in hexanes) to yield88-6. LCMS-ESI (m/z): [M+H]⁺ calcd for C₃₃H₄₂ClF₂N₄O₆: 663.27. found:663.33.

Step 7. Preparation of mixture of 88-7: Rhodium on alumina (5 wt % Rh,31 mg, 0.015 mmol) was added to a solution of 88-6 (90 mg, 0.136 mmol)in 9 mL of ethanol. The atmosphere was replaced with hydrogen andmixture was stirred overnight. The reaction was filtered over Celite,washing with ethanol. LC/MS analysis indicated about 60% startingmaterial remained. A solution of the residue in 8 mL of ethanol wasresubjected to hydrogenation conditions utilizing 25 mg of Rhodium onalumina (5 wt % Rh) overnight. The reaction was filtered over Celite,washing with ethanol. Filtrate was concentrated in vacuo to yield asresidue, which was purified via silica gel column chromatography (0-30%ethyl acetate in hexanes) to yield 88-7. LCMS-ESI (m/z): [M+H]⁺ calcdfor C₃₃H₄₄ClF₂N₄O₆: 665.28. found: 665.48.

Step 8. Preparation of 88-8: TFA (0.45 mL, 5.86 mmol) was added slowlyto a solution of 88-7 (52 mg, 0.078 mmol) in 2 mL of dichloromethane.After 3 hours, mixture was concentrated under reduced pressure to neardryness. Resulting residue was taken up in 10 mL of ethyl acetate,washed with 8 mL of water, 8 mL of sat. NaHCO_(3 (aq)), and separated.Aqueous layers were extracted with ethyl acetate (3×10 mL). Combinedorganics were washed with 10 mL of brine, dried over anhydrous MgSO₄,filtered, and concentrated in vacuo to yield 88-8, which was used in thenext step without further purification. LCMS-ESI (m/z): [M+H]⁺ calcd forC₂₉H₃₆ClF₂N₄O₆: 609.22. found: 609.42.

Step 9. Preparation of Example 88: HATU (58 mg, 0.153 mmol, Oakwood) andDIPEA (0.065 mL, 0.374 mmol) were added to a mixture of 88-8 (45 mg,0.074 mmol) and Intermediate A10 (49 mg, 0.161 mmol) in 2.5 mL ofacetonitrile under argon. After stirring for overnight, reaction mixturewas taken up in 15 mL of ethyl acetate and washed with 10 mL of 1 Naqueous HCl. The aqueous layer was extracted three times with ethylacetate. Combined organics were washed with 50% brine, dried overanhydrous Na₂SO₄, filtered, and concentrated in vacuo. The resultingresidue was purified by silica gel chromatography (0-50% ethyl acetatein hexanes) and reverse phase prep HPLC (50-100% acetonitrile in water,with 0.1% trifluoroacetic acid buffer) to yield the trifluoroacetic acidsalt of Example 88. Analytic HPLC RetTime: 8.92 min. LCMS-ESI⁺ (m/z):[M+H]⁺ calcd for C₃₈H₄₈ClF₄N₆O₈S: 859.28. found: 859.42. ¹H NMR (400MHz, CD₃OD): δ 9.23 (s, 1H), 8.10 (s, 1H), 7.90 (d, J=8.8 Hz, 1H), 7.81(d, J=8.8 Hz, 1H), 5.81 (td, J_(H-F)=56 Hz, J=6.0 Hz, 1H), 5.69-5.66 (m,1H), 4.56 (d, J=7.2 Hz, 1H), 4.43 (d, J=12 Hz, 1H), 4.34 (s, 1H),4.22-4.16 (dd, J=12, 4 Hz, 1H), 3.71-3.66 (m, 1H), 2.83-2.76 (m, 1H),2.61-2.48 (m, 1H), 2.11-1.94 (m, 4H), 1.88-1.72 (m, 4H), 1.71-1.62 (m,1H), 1.58-1.54 (m, 2H), 1.51 (s, 3H), 1.50-1.36 (m, 2H), 1.09 (s, 9H),1.08-1.01 (m, 3H), 1.01-0.94 (m, 2H), 0.93-0.86 (m, 2H), 0.80-0.68 (m,1H), 0.52-0.46 (m, 1H).

Example 89 Preparation of(1aR,5S,8S,9S,10R,19E,22aR)-5-tert-butyl-N-[(1R,2R)-2-(difluoromethyl)-1-{[(1-methylcyclopropyl)sulfonyl]carbamoyl}cyclopropyl]-9-ethyl-18,18-difluoro-14-methoxy-3,6-dioxo-1,1a,3,4,5,6,9,10,18,21,22,22a-dodecahydro-8H-7,10-methanocyclopropa[18,19][1,10,3,6]dioxadiazacyclononadecino[11,12-b]quinoxaline-8-carboxamide

Step 1. Preparation of 89-1: 17-4 (95 mg, 0.14 mmol) in 0.4 mL DCM wastreated with 0.4 mL TFA and stirred at rt for 2 h. The reaction mixturewas diluted with 5 mL DCM and then treated with water and saturatedsodium bicarbonate to pH 6.5. The layers were separated and the organicphase was washed once more with water, then dried over anhydrous sodiumsulfate, filtered and concentrated to give 89-1. LCMS-ESI (m/z): [M+H]⁺calcd for C₃₁H₃₉F₂N₄O₇: 617.3. found: 616.7.

Step 2. Preparation of Example 89: A mixture of 89-1 from step 1 (41 mg,0.066 mmol), Intermediate A10 (24 mg, 0.079 mmol), HATU (30 mg, 0.079mmol), and DIPEA (0.057 mL, 0.33 mmol) in DMF (0.4 mL) was stirred at rtovernight. The mixture was diluted with 2N HCl (1 mL) and extracted withdichloromethane. The organic phase was dried over sodium sulfate,filtered and concentrated. The crude product mixture was purified byreverse phase prep HPLC (10-99% acetonitrile in water, with 0.1%trifluoroacetic acid buffer) to give Example 89. Analytic HPLC RetTime:8.65 min. LCMS-ESI (m/z): [M+H]⁺ calcd for C₄₀H₅₁F₄N₆O₉S: 867.3. found:866.9. ¹H NMR (400 MHz, CDCl₃) δ 9.890 (s, 1H), 7.98 (d, J=9.2 Hz, 1H),7.28 (dd, J=8.8, 2.4 Hz, 1H), 7.06 (d, J=2.8 Hz, 1H), 6.75 (br s, 1H),6.30-5.93 (m, 2H), 5.92 (td, J_(H-F)=52 Hz, J=6.8 Hz, 1H), 5.47 (d, J=10Hz, 1H), 4.53 (d, J=12 Hz, 1H), 4.48 (d, J=10.4 Hz, 1H), 4.42 (d, J=6.8Hz, 1H), 4.07 (dd, J=11.6, 3.2 Hz, 1H), 3.98-3.94 (m, 1H), 3.95 (s, 3H),3.57 (m, 1H), 2.60-2.48 (m, 2H), 2.20 (m, 1H), 2.06 (m, 1H), 1.90 (m,1H), 1.80 (m, 1H), 1.63 (m, 2H), 1.50 (s, 3H), 1.56-1.36 (m, 2H), 1.26(m, 1H), 1.19 (t, J=7.2 Hz, 3H), 1.09 (s, 9H), 1.03-0.93 (m, 2H), 0.85(m, 2H), 0.76 (m, 1H), 0.53 (m, 1H).

Example 90 Preparation of(1aR,5S,8S,9S,10R,22aR)-5-tert-butyl-N-[(1R,2R)-2-(difluoromethyl)-1-{[(1-methylcyclopropyl)sulfonyl]carbamoyl}cyclopropyl]-9-ethyl-18-fluoro-14-methoxy-3,6-dioxo-1,1a,3,4,5,6,9,10,18,19,20,21,22,22a-tetradecahydro-8H-7,10-methanocyclopropa[18,19][1,10,3,6]dioxadiazacyclononadecino[11,12-b]quinoxaline-8-carboxamide

Further purification of a synthesis of compound 17 by reverse phase prepHPLC (60-88% acetonitrile in water, with 0.1% trifluoroacetic acidbuffer) allowed isolation of example 93 as a minor side product.Analytic HPLC RetTime: 8.64 min. LCMS-ESI (m/z): [M+H]⁺ calcd forC₄₀H₅₄F₃N₆O₉S: 851.4. found: 851.4. ¹H NMR (400 MHz, CDCl₃) δ 9.93 (brs, 1H), 7.88 (d, J=9.1 Hz, 1H), 7.22 (d, J=2.4 Hz, 1H), 7.06 (d, J=2.4Hz, 1H), 6.55 (s, 1H), 5.91 (td, J_(H-F)=136 Hz, J=8 Hz, 1H), 5.81 (td,J_(H-F)=52 Hz, J=8 Hz, 1H), 5.30 (d, J=9.7 Hz, 1H), 4.44 (d, J=12.0 Hz,1H), 4.38 (d, J=6.7 Hz, 1H), 4.32 (d, J=9.8 Hz, 1H), 4.07 (m, 1H), 3.93(s, 3H), 3.72 (m, 1H), 2.59 (m, 1H), 2.35 (m, 1H), 2.06 (m, 4H), 1.88(m, 1H), 1.78 (m, 1H), 1.71-1.52 (m, 4H), 1.48 (s, 3H), 1.48-1.41 (m,2H), 1.23 (m, 2H) 1.21 (t, J=8.0 Hz, 3H), 1.08 (s, 9H), 1.05-0.90 (m,2H), 0.84 (m, 2H), 0.66 (m, 1H), 0.48 (m, 1H).

Example 91 Preparation of(1aR,5S,8S,9S,10R,22aR)-5-tert-butyl-N-{(1R,2S)-1-[(cyclopropylsulfonyl)carbamoyl]-2-ethenylcyclopropyl}-9-ethyl-14-methoxy-3,6-dioxo-1,1a,3,4,5,6,9,10,18,19,20,21,22,22a-tetradecahydro-8H-7,10-methanocyclopropa[18,19][1,10,3,6]dioxadiazacyclononadecino[11,12-b]quinoxaline-8-carboxamide

Example 91 was prepared similarly to Example 1 substituting IntermediateA1 for Intermediate A10 in Step 8. The TFA salt of Example 91 wasisolated. Analytic HPLC RetTime: 8.72 min. LCMS-ESI⁺ (m/z): [M+H]⁺ calcdfor C₄₀H₅₅N₆O₉S: 795.96. found: 795.94. ¹H NMR (400 MHz, CD₃OD) δ 9.03(s, 1H); 7.80 (d, J=9.2 Hz, 1H); 7.24 (dd, J=9.2, 2.4 Hz, 1H); 7.16 (d,J=2.4 Hz, 1H); 5.90 (d, J=3.6 Hz, 1H); 5.68 (m, 1H); 5.25 (d, J=17.2 Hz,1.6 Hz, 1H); 5.10 (d, J=11.2, 1.6 Hz, 1H); 4.57 (d, J=6.8 Hz, 1H); 4.39(br s, 1H); 4.37 (d, J=9.2 Hz, 1H); 4.16 (dd, J=12.8, 4.4 Hz, 1H); 3.93(s, 3H); 3.77-3.72 (m, 1H); 3.02-2.88 (m, 1H): 2.86-2.75 (m, 1H);2.64-2.54 (m, 1H); 2.18 (q, J=8.8 Hz, 1H): 1.90-1.66 (m, 4H); 1.66-1.40(m, 6H); 1.38-1.32 (m, 1H); 1.30-1.20 (m, 5H); 1.10 (s, 9H); 1.14-1.02(m, 2H); 0.77-0.68 (m, 1H); 0.54-0.45 (m, 1H).

Example 92 Preparation of(1aR,5S,8S,9S,10R,22aR)-5-tert-butyl-N-{(1R,2S)-1-[(cyclopropylsulfonyl)carbamoyl]-2-ethenylcyclopropyl}-9-ethyl-18,18-difluoro-14-methoxy-3,6-dioxo-1,1a,3,4,5,6,9,10,18,19,20,21,22,22a-tetradecahydro-8H-7,10-methanocyclopropa[18,19][1,10,3,6]dioxadiazacyclononadecino[11,12-b]quinoxaline-8-carboxamide

Example 92 was prepared in a similar fashion to Example 17, substitutingIntermediate A1 for Intermediate A10 in Step 7. Example 92 was isolated.Analytic HPLC RetTime: 8.75 min. LCMS-ESI⁺ (m/z): [M+H]⁺ calcd forC₄₀H₅₃F₂N₆O₉S: 831.36. found: 831.25. ¹H NMR (400 MHz, Chloroform-d) δ9.98 (s, 1H), 7.96 (d, J=9.2 Hz, 1H), 7.40-7.19 (m, 1H), 7.08 (s, 1H),6.56 (s, 1H), 5.91 (d, J=3.8 Hz, 1H), 5.86-5.64 (m, 1H), 5.34 (d, J=9.7Hz, 1H), 5.21 (d, J=17.2 Hz, 1H), 5.10 (d, J=10.3 Hz, 1H), 4.53-4.26 (m,2H), 4.15-4.02 (m, 1H), 3.95 (s, 3H), 3.73-3.57 (m, 1H), 2.97-2.81 (m,1H), 2.64-2.37 (m, 2H), 2.21-2.06 (m, 1H), 2.06-1.88 (m, 2H), 1.88-1.55(m, 4H), 1.55-1.12 (m, 10H), 1.07 (s, 9H), 1.02-0.78 (m, 5H), 0.78-0.61(m, 1H), 0.47 (q, J=7.3, 6.2 Hz, 1H).

Example 93 Preparation of(1aR,5S,8S,9S,10R,22aR)-5-tert-butyl-9-ethyl-N-[(2R)-2-ethyl-1-{[(1-methylcyclopropyl)sulfonyl]carbamoyl}cyclopropyl]-18,18-difluoro-14-methoxy-3,6-dioxo-1,1a,3,4,5,6,9,10,18,19,20,21,22,22a-tetradecahydro-8H-7,10-methanocyclopropa[18,19][1,10,3,6]dioxadiazacyclononadecino[11,12-b]quinoxaline-8-carboxamide

Example 93 was prepared in a similar fashion to Example 17, substitutingIntermediate A4 for Intermediate A10 in Step 7. Example 93 was isolated.Analytic HPLC RetTime: 8.03 min. LCMS-ESI (m/z): [M+H]⁺ calcd forC₄₁H₅₇F₂N₆O₉S: 847.39. found: 846.99. ¹H NMR (400 MHz, cdcl₃) δ 7.95 (d,J=8.9 Hz, 1H), 7.27 (m, 1H), 7.08 (s, 1H), 6.65 (s, 1H), 5.91 (s, 1H),5.41 (d, J=9.0 Hz, 1H), 4.82 (m, 2H), 4.47 (d, J=6.2 Hz, 1H), 4.35 (dd,J=35.7, 10.7 Hz, 2H), 4.07 (m, 1H), 3.94 (s, 3H), 3.63 (m, 1H), 2.50 (m,2H), 1.95 (m, 2H), 1.94 (m, 2H), 1.78 (m, 3H), 1.64 (m, 4H), 1.48 (m,6H), 1.19 (m, 4H), 1.07 (s, 9H), 1.05-0.88 (m, 4H), 0.88-0.75 (m, 1H),0.67 (m, 1H), 0.47 (m, 1H).

Example 94 Preparation of(1aR,5S,8S,9S,10R,22aR)-5-tert-butyl-N-[(2R)-1-[(cyclopropylsulfonyl)carbamoyl]-2-(difluoromethyl)cyclopropyl]-9-ethyl-18,18-difluoro-14-methoxy-3,6-dioxo-1,1a,3,4,5,6,9,10,18,19,20,21,22,22a-tetradecahydro-8H-7,10-methanocyclopropa[18,19][1,10,3,6]dioxadiazacyclononadecino[11,12-b]quinoxaline-8-carboxamide

Example 94 was prepared in a similar fashion to Example 17, substitutingIntermediate A9 for Intermediate A10 in Step 7. Example 94 was isolated.Analytic HPLC RetTime: 8.71 min. LCMS-ESI⁺ (m/z): [M+H]⁺ calcd forC₃₉H₅₁F₄N₆O₉S: 855.34. found: 855.26. ¹H NMR (400 MHz, CDCl₃) (10.22 (s,1H), 8.02 (d, J=9.2 Hz, 1H), 7.33 (d, J=12 Hz, 1H), 7.12 (s, 1H), 5.95(td, J_(HF)=52 Hz, J=8 Hz, 1H), 5.50 (d, J=9.7 Hz, 1H), 4.53 (d, J=6.4Hz, 1H), 4.46 (dd, J=26.4, 10.7 Hz, 2H), 4.13 (d, J=11.5 Hz, 1H), 4.00(s, 3H), 3.68 (m, 1H), 2.91 (m, 1H), 2.57 (m, 3H), 2.13 (m, 2H), 1.94(m, 2H), 1.73 (m, 3H), 1.50 (m, 3H), 1.33 (m, 3H), 1.22 (t, J=7.2 Hz,3H), 1.13 (s, 9H), 1.00-0.95 (m, 4H), 0.95-0.85 (m, 1H), 0.69 (m, 1H),0.51 (m, 1H).

Example 95 Preparation of(1aS,2aR,6S,9S,10S,11R,23aR,23bS)-6-tert-butyl-15-cyano-N-[(1R,2R)-2-(difluoromethyl)-1-{[(1-methylcyclopropyl)sulfonyl]carbamoyl}cyclopropyl]-19,19-difluoro-10-methyl-4,7-dioxo-1a,2,2a,4,5,6,7,10,11,19,20,21,22,23,23a,23b-hexadecahydro-1H,9H-8,11-methanocyclopropa[4′,5′]cyclopenta[1′,2′:18,19][1,10,3,6]dioxadiazacyclononadecino[11,12-b]quinoxaline-9-carboxamide

Intermediate 95-1 was prepared in a similar fashion to Intermediate46-2, substituting E6 for Intermediate E3 in Step 1. LCMS-ESI⁺ (m/z):[M+H]⁺ calcd for C₂₇H₃₃F₂N₄O₅: 531.24. found: 531.2.

Example 95 was prepared in a similar fashion to Example 62, substitutingIntermediate 95-1 for Intermediate 46-2 in Step 1 and substitutingIntermediate A10 for Intermediate A9 in Step 5. Example 95 was isolated.Analytic HPLC RetTime: 8.86 min. LCMS-ESI⁺ (m/z): [M+H]⁺ calcd forC₄₂H₅₂F₄N₇O₈S: 890.35. found: 889.94. ¹H NMR (400 MHz, CDCl₃) δ 9.34 (s,1H), 7.80 (m, 2H), 7.42 (d, J=8.6 Hz, 1H), 6.85 (s, 1H), 6.69 (s, 1H),5.38 (m, 1H), 5.29 (m, 3H), 5.02 (d, J=8.8 Hz, 1H), 4.46 (d, J=7.4 Hz,1H), 4.10-3.97 (m, 2H), 3.84 (d, J=7.9 Hz, 1H), 3.74 (d, J=8.6 Hz, 1H),2.42-2.29 (m, 1H), 2.10 (s, 1H), 1.87-1.72 (m, 1H), 1.69-1.48 (m, 4H),1.38 (d, J=14.8 Hz, 2H), 1.30-1.08 (m, 4H), 0.99 (s, 5H), 0.89 (m, 3H),0.69 (s, 10H), 0.64 (m, 1H), 0.43 (s, 1H), 0.11 (m, 1H), 0.01 (m, 1H).

Example 96 Preparation of(1aS,2aR,6S,9S,10S,11R,21E,24aR,24bS)-6-tert-butyl-15-chloro-N-[(1R,2R)-2-(difluoromethyl)-1-{[(1-methylcyclopropyl)sulfonyl]carbamoyl}cyclopropyl]-10-methyl-4,7,18-trioxo-1a,2,2a,4,5,6,7,10,11,20,23,24,24a,24b-tetradecahydro-1H,9H,18H-8,11-methanocyclopropa[4′,5]cyclopenta[1′,2′:18,19][1,10,3,6,12]dioxatriazacyclononadecino[11,12-b]quinazoline-9-carboxamide

Example 96 was prepared in a similar fashion to Example 89, substitutingintermediate 96-1 for intermediate 17-4 in Step 1. Intermediate 96-1 wasprepared in a similar fashion to intermediate 17-4 of Example 17,substituting E9 for E3 and B1 for B4 in Step 1, and substitutingintermediate D16 for intermediate 011 in Step 3. Example 96 wasisolated. Analytic HPLC RetTime: 9.18 min. LCMS-ESI⁺ (m/z): [M+H]⁺ calcdfor C₄₁H₅₂C₁F₂N₆O₉S: 877.32. found: 877.61. ¹H NMR (400 MHz,Chloroform-d) δ 9.76 (s, 1H), 8.03 (d, J=8.6 Hz, 1H), 7.39 (m, 1H), 7.27(m, 1H), 6.80 (s, 1H), 5.92 (m, 1H), 5.87-5.73 (m, 1H), 5.68 (m, 1H),5.64-5.51 (m, 1H), 5.21 (m, 1H), 4.93 (m, 2H), 4.52-4.32 (m, 3H),4.15-3.94 (m, 2H), 2.86-2.71 (m, 1H), 2.26 (m, 1H), 2.15 (m, 2H),2.10-2.02 (m, 1H), 2.02-1.84 (m, 2H), 1.77 (m, 2H), 1.61 (s, 3H), 1.50(m, 4H), 1.42-1.17 (m, 6H), 1.17-0.92 (m, 10H), 0.92-0.78 (m, 2H),0.51-0.37 (m, 1H).

Example 97 Preparation of(1aS,2aR,6S,9S,10S,11R,23aR,23bS)-6-tert-butyl-15-cyano-N-[(2R)-2-(difluoromethyl)-1-{[(1-methylcyclopropyl)sulfonyl]carbamoyl}cyclopropyl]-10-methyl-4,7-dioxo-1a,2,2a,4,5,6,7,10,11,19,20,21,22,23,23a,23b-hexadecahydro-1H,9H-8,11-methanocyclopropa[4′,5]cyclopenta[1′,2′:18,19][1,10,3,6]dioxadiazacyclononadecino[11,12-b]quinoxaline-9-carboxamide

Intermediate 97-1 was prepared in a similar fashion to intermediate79-5, substituting E2 for E5 in Step 1. LCMS-ESI⁺ (m/z): [M+H]⁺ calcdfor C₄₃H₅₅N₄O₇: 739.41. found: 739.31.

Step 1. Preparation of 97-2. Macrocyclic olefin 97-1 (0.84 g, 1.14 mmol)was dissolved in 114 mL ethanol and 114 mL ethyl acetate. Afterdegassing with Argon, 0.84 g of 5% Pd/C Degussa-type was added and themixture was hydrogenated for 4 hours at 1 atm. Filtration throughcelite, concentration, and silica gel chromatography (40%-60% ethylacetate in hexanes gradient) provided intermediate 97-2. LCMS-ESI (m/z):[M+H]⁺ calcd for C₃₆H₅₁N₄O₇: 651.38. found: 651.32.

Step 2. Preparation of 97-3. An ice cold solution of macrocycle phenol97-2 (0.47 g, 0.73 mmol) and triethylamine (0.81 ml, 5.81 mmol) in 3 mLDCM was treated with trifluoromethanesulfonic anhydride solution, 1M inmethylene chloride (0.18 ml, 1.09 mmol) dropwise. After stirring for 2hours, the reaction was quenched with water and extracted with ethylacetate. The organic layer was washed with water and brine, dried overNa₂SO₄, filtered and concentrated. Silica gel chromatography using a5%-50% ethyl acetate in hexanes gradient gave 97-3 as the first elutingpeak (55 mg). LCMS-ESI⁺ (m/z): [M+H]⁺ calcd for C₃₇H₅₀F₃N₄O₉S: 783.33.found: 782.96.

Step 3. Preparation of 97-4. Degassed a mixture of macrocycle triflate97-3 (408 mg, 0.52 mmol), tetrakis(triphenylphosphine)palladium (30.11mg, 0.03 mmol), Zinc cyanide, 98% (61.21 mg, 0.52 mmol) in 2.6 mL DMFfor 10 minutes. The reaction was heated at 80° C. for 1 hour. Anadditional 60 mg tetrakis(triphenylphosphine)palladium and 120 mg Zinccyanide were added and heating was continued for 30 minutes. Thereaction was quenched with saturated ammonium chloride solution andextracted with ethyl acetate. The organic phase was separated, driedover anhydrous sodium sulphate, filtered and concentrated. The crudeproduct was purified by silica gel chromatography using a gradient of5%-70% ethyl acetate in hexanes to give intermediate 97-4. LCMS-ESI⁺(m/z): [M+H]⁺ calcd for C₃₇H₅₀N₅O₆: 660.38. found: 660.10.

Step 4. Preparation of 97-5. A solution of 97-4 (290 mg, 0.44 mmol) in 1mL DCM was treated with 0.5 mL of TFA and stirred overnight. Water wasadded and the mixture was extracted with ethyl acetate. The organicphase was separated, dried over anhydrous sodium sulphate, filtered andconcentrated. The crude product was purified by silica gelchromatography using a gradient of 10%-70% ethyl acetate in hexanes togive intermediate 97-5 (216 mg) as a white solid. LCMS-ESI (m/z): [M+H]⁺calcd for C₃₃H₄₂N₅O₆: 604.31. found: 604.00.

Step 5. Preparation of Example 97. A mixture of 97-5 (50 mg, 0.08 mmol),HATU (37.79 mg, 0.1 mmol), in 0.3 mL DMF was stirred 5 min, then A10 (50mg, 0.08 mmol) and DIPEA (0.06 ml, 0.33 mmol) were added. After 45 minat rt, the reaction was incomplete (LCMS). Added another 20 mg of A10and stirred for 2 hours. 2 mL of 1N HCl was added, and the mixture wasextracted with DCM. The crude product was purified by silica gelchromatography using a gradient of 30%-65% ethyl acetate in hexanes.Combined product fractions contained some residual DMF. Water was added,which generated a precipate (14 mg). The filtrate was extracted withethyl acetate, and the extracts were combined with the precipitate. Theresulting solution was dried over anhydrous sodium sulphate, filtered,concentrated and dried under reduced pressure to give Example 97.Analytic HPLC RetTime: 9.06 min. LCMS-ESI (m/z): [M+H]⁺ calcd forC₄₂H₅₄F₂N₇O₈S: 854.98. found: 853.88. ¹H NMR (400 MHz, CDCl₃) δ 9.77 (brs, 1H), 8.05 (m, 1H), 7.93 (m, 1H), 7.62 (m, 1H), 7.20 (m, 1H), 7.08 (m,1H), 6-5.65 (m, 1H), 5.56 (m, 1H), 5.17 (m, 1H), 4.90 (m, 1H), 4.38 (m,2H), 4.22 (m, 1H), 4.06 (m, 1H), 3.57 (m, 1H), 2.88 (m, 1H), 2.70 (m,5H), 2.28-2.08 (m, 1H), 2.04-1.30 (m, 12H), 1.29-1.09 (m, 9H), 1.08-0.96(m, 4H), 0.85-0.67 (m, 3H), 0.43 (m, 1H), 0.34 (m, 1H), 0.19-0.03 (m,1H).

The following compounds can be made with the synthetic methods of thisdisclosure, or by means generally well known in the art:

wherein V is a structure of Formula:

and wherein E and G are defined as above.

Biological Activity Expression and Purification of Genotype 1a, 2a, and3 NS3 Proteases Generation of NS3 Protease Expression Plasmids

The coding sequence of the genotype 1b (con-1 strain) HCV NS3 proteasedomain was PCR amplified from a plasmid encoding theI389luc-ubi-neo/NS3-3′/ET replicon (Reblikon, Mainz, Germany). The5′-PCR primer was designed to encode an N-terminal K₃ hexahistidine tagand to insert an in-frame recombinant Tobacco Etch virus (rTEV) proteasecleavage site into the NS3 coding sequence. The resulting DNA fragmentwas cloned into the pET28 protein expression vector (Invitrogen,Carlsbad, Calif.) yielding the p28-N6H-Tev-NS3(181)1b.

The coding sequences for the genotype 3 HCV protease domain wasamplified by RT-PCR using a Titan One Tube RT-PCR Kit (Roche,Indianapolis, Ind.) and RNA extracted from HCV-positive human serum (BBIDiagnostics, MA) using a QIAmp UltraSens Virus Kit (Qiagen, Valencia,Calif.). 5′ PCR primers were designed to encode N-terminal hexahistidinetags and to insert in-frame rTEV protease cleavage sites into the NS3protease coding sequences. The resulting DNA fragments were cloned intopET28 yielding the expression vectors p28-N6H-Tev-NS3(181)1a andp28-N6H-Tev-NS3(181)3, respectively.

NS3 Protease Protein Expression

BL21AI bacteria (Invitrogen, Carlsbad, Calif.) were transformed withgenotype 1b or 3 NS3 expression vectors and used to inoculate a 20 Lfermentation vessel (Sartorius BBI System Inc., Bethlehem, Pa.),containing 18 L of fresh 2YT medium supplemented with 50 μg/mlkanamycin. When cell densities reached an OD₆₀₀ of 1, the temperature ofthe cultures was reduced from 37° C. to 280 C and induction wasimmediately initiated by the addition of 30 μM ZnSO₄, 14 mM L-arabinoseand 1 mM Isopropyl β-D-thiogalactoside (IPTG) final concentrations.Cells were harvested by centrifugation four hours post-induction andwere stored as frozen pellets at −80° C. prior to NS3 proteinpurification.

Purification of NS3 Proteases Purification of Genotype 1b NS3 Protease

Cell pellets were thawed and resuspended at 10 ml/g cells in lysisbuffer containing 50 mM tris pH 7.6, 300 mM NaCl, 0.1%3-[(3-Cholamidopropyl)dimethylammonio]-1-propanesulfonate (CHAPS), 5%glycerol, and 2 mM β-mercaptoethanol. Cell suspensions were thensonicated, filtered through cheesecloth, and passed three times througha microfluidizer at 18,000 pounds/in². The resulting lysates werecentrifuged at 15500 rpm for 45 minutes and supernatants were loadedonto a HisTrap HP column (GE Lifesciences) pre-equilibrated with fivevolumes of Ni buffer A (50 mM tris pH 7.6, 300 mM NaCl, 0.1% CHAPS, 5%glycerol, 2 mM β-mercaptoethanol, 50 mM imidazole-HCl). Proteins wereeluted with a 0-100% gradient of Ni buffer A plus 500 mM imidazole-HCland fractions were collected and pooled. The HisTrap pool was diluted1:10 with SP-A buffer (50 mM tris pH 7.0, 10% glycerol, 2 mMdithiothreitol (DTT)) and loaded onto a HiTrap SP-HP column (GELifesciences) equilibrated with SP-A buffer. NS3 protease was elutedwith a 0-100% SP-B buffer (SP-A buffer plus 1 M NaCl) gradient.Concentrated pools of NS3-containing SP fractions were aliquoted, snapfrozen in liquid nitrogen and stored at −80° C.

Purification of Genotype 3 NS3 Protease

Bacterial pellets collected from the expression of genotype 3 HCV NS3protease were homogenized in Lysis Buffer (25 mM tris, pH 7.5 buffercontaining 150 mM NaCl and 1 mM phenylmethanesulfonyl fluoride (PMSF))and passed through a microfluidizer at 18,000 pounds/in². Homogenizedcell lysates were centrifuged at 30,000×g for 30 minutes at 4° C. Theresulting P1 pellets were washed with Wash Buffer I (25 mM tris, pH 7.5containing 1% CHAPS) followed by centrifugation at 10,000×g for 30minutes at 4° C. The resulting P2 pellets were washed with Wash BufferII (50 mM CAPS buffer, pH 10.8, containing 2M NaCl and 2M urea) followedby centrifugation at 30,000×g for minutes at 4° C. The resulting P3pellets were resuspended in Solubilization Buffer (20 ml of 25 mM tris,pH 7.5 containing 150 mM NaCl and 8 M urea) and incubated at 4° C. forone hour. Solubilized proteins were passed through a 0.45 micron filter.Protein concentrations were measured and the solutions were adjusted to40 mM DTT, incubated for 30 minutes at 4° C. and then quickly dilutedinto Refolding Buffer (25 mM tris, pH 8.5, 0.8 M Guanidine-HCl, 0.4 ML-Arginine, 10 mM ZnSO₄) while stirring. Protein solutions wereincubated at 4° C. overnight to allow refolding. Refolded proteases werecentrifuged at 30,000×g for 10 minutes to remove residual precipitates.Final protein concentrations were then measured and the NS3 proteaseswere aliquoted, snap frozen in liquid nitrogen and stored at −80° C.

Ki Determination for Genotypes 1b and 3a NS3 Protease.

Purified NS3 protease domain (amino acids 1-181) of the genotype 1b and3a virus were generated as above. The internally quenched fluorogenicdepsipeptide substrate Ac-DED(Edans)-EEAbuΨ[COO]ASK(Dabcyl)-NH₂ and asynthetic peptide containing the hydrophobic core residues of the NS4Aprotein cofactor (KKGSVVIVGRIILSGRKK; NS4A peptide) were obtained fromAnaspec, Inc. (San Jose, Calif.). Other chemicals and biochemicals wereof reagent grade or better and were purchased from standard suppliers.

Reactions were run at room temperature in buffer consisting of 50 mMHEPES, 40% glycerol, 0.05% Triton X-100, 10 mM DTT, and 10% DMSO. Thefinal assay solutions contained 50 μM NS3 genotype 1b protease or 200 μMgenotype 3a protease, 20 μM NS4A peptide, and 4 μM substrate (genotype1b) or 2 μM substrate (genotype 3a). Inhibitor concentrations variedfrom 100 nM to 5 μM in 3-fold dilutions, and no-inhibitor controls wereincluded.

Compound dilutions were made in DMSO at 20× final concentration.Reaction mixtures were prepared in 96-well assay plates. A solution ofenzyme and NS4A peptide in assay buffer (25 μL volume with both reagentsat 4× final concentration) was mixed with 45 μL assay buffer and 5 μL ofeither inhibitor or DMSO, and pre-incubated at room temperature for 1hour. The reaction was started by addition of 25 μL substrate solutionat 4× final concentration. Plates were mixed vigorously for 5-10 secondsand reactions were allowed to proceed for 90 minutes. fluorescence wasmeasured every 30 s between 90 and 120 minutes reaction time using aTecan InfiniTe M1000 or PerkinElmer Envision multimode plate reader withan excitation wavelength of 340 nm and an emission wavelength of 490 nm.

Rates were calculated from the progress curves at steady state, in thetime frame of 90-120 minutes after addition of substrate. To determinethe K, rates were plotted as a function of inhibitor concentration, andthe data were fit with equation 1 (Morrison, J. F., Biochimica etBiophysica Acta 1969, 185, 269-286) to calculate K_(i) ^(app) usingGraphPad Prism 5. Active fraction of enzyme was determined by activesite titration with known potent inhibitors. K was calculated from K_(i)^(app)/(1+[[S]/K_(m)]). Ki results for representative compounds forgenotype 1b and 3a (Ki 1B and Ki 3A, respectively) are reported in Table1.

$\begin{matrix}{\frac{v}{v_{0}} = \frac{\lbrack E\rbrack_{t} - \lbrack I\rbrack_{t} - K_{i}^{app} + \sqrt{\left( {\lbrack E\rbrack_{t} - \lbrack I\rbrack_{t} - K_{i}^{app}} \right)^{2} + {{4\lbrack E\rbrack}_{t}K_{i}^{app}}}}{{2\;\lbrack E\rbrack}_{t}}} & (1)\end{matrix}$

Evaluation of Cell-Based Anti-HCV Activity:

Antiviral potency (EC₅₀) was determined in both stable subgenomic HCVreplicon cell lines and transient-transfected HCV replicon cells. Theterm half maximal effective concentration (EC₅₀) refers to theconcentration of a drug which induces a response halfway between thebaseline and maximum after the exposure time specified below.

Stable subgenomic HCV replicons for genotype 1a, 1b, 2a, 3a, and 4a wereestablished in Huh-7-derived cells as described by Lohmann et al(Lohmann V, Korner F, Koch J, et al Replication of subgenomic hepatitisC virus RNAs in a hepatoma cell line. Science 1999; 285:119-3). Eachstable cell line contains a bicistronic HCV replicon that encodes ahumanized Renilla luciferase (hRLuc) reporter gene fused to a selectableneomycin-resistance gene, followed by an EMCV IRES and the NS3-NS5Bcoding region of HCV. Selection for cells constitutively expressing theHCV replicon was achieved in the presence of the selection antibiotic,neomycin (G418). Luciferase activity was measured as a marker forintracellular HCV replication levels.

The genotype 1a stable replicon was derived from the H77 HCV strain andcontained adaptive mutations P1496L and S2204I. The genotype 1b stablereplicon was derived from the Con1 HCV strain and contained adaptivemutations E1202G, T1280I, and K1846T. The genotype 2a stable repliconwas derived from the JFH-1 HCV strain and did not require adaptivemutations. The genotype 3a stable replicon was derived from the S52 HCVstrain and contained adaptive mutations P1121L, A1198T and S2210I(equivalent to S2204I in genotype 1). The genotype 4a stable repliconwas derived from the ED43 HCV strain and contained adaptive mutationsQ1691R and S2204I. All replicon cell lines were propagated inHuh-7-derived cells and maintained in Dulbecco's modified Eagle's Medium(DMEM) supplemented with 10% fetal bovine serum (FBS) and 0.5 mg/mlG418.

Transient-transfected HCV replicons were established for genotype 1a,1b, 3a and NS3/4a protease inhibitor resistant variants D168A ingenotype 1b or R155K in genotype 1a. Transient-transfected replicons arealso biscistronic subgenomic replicons but do not contain the neomycinselectable marker present in stable replicons. These replicons encodethe poliovirus IRES followed by the hRLuc reporter gene, the EMCV IRESand finally the NS3-NS5B coding region of HCV. The genotype 1a (H77) and1b (Con1) wild-type replicons were derived from the same strain andcontained the same adaptive mutations as listed above. The genotype 3atransient replicon was derived from the S52 HCV strain as above, butcontained slightly different adaptive mutations P1112L, K1615E andS2210I. Specifically, the secondary adaptive mutation A1198T (A166T) inthe protease domain of the stable genotype 3a replicon was replaced withK1615E (K583E) in the NS3 helicase, with no effect on replicationefficiency. Removal of A166T located in the protease domain minimizesthe impact of this variant on inhibitors targeting the protease domainand represents a protease domain closer to wild type for genotype 3a.Resistant replicons encoding NS3/4 protease inhibitor mutations wereintroduced into the 1b or 1a wild-type NS3 gene by site directedmutagenesis. In vitro transcribed RNAs from all transient replicons weretransfected into naive Huh-7-derived cell lines by electroporation.Luciferase activity was measured as a marker for intracellular HCVreplication levels

To perform EC₅₀ assays, cells from each HCV replicon were dispensed into384-well plates. Compounds were dissolved in DMSO at a concentration of10 mM and diluted in DMSO using an automated pipetting instrument.Three-fold serially diluted compounds were directly added to the cellsusing an automated instrument. DMSO was used as a negative (solvent; noinhibition) control, and a combination of three HCV inhibitors includinga protease inhibitor; an NS5A inhibitor and a nucleoside inhibitor wasused at concentrations >100× EC₅₀ as a positive control (100%inhibition). Seventy-two hours later, cells were lysed and Renillaluciferase activity were quantified as recommended by the manufacturer(Promega-Madison, Wis.). Non-linear regression was performed tocalculate EC₅₀ values.

Results are shown in Tables 1 and 2:

TABLE 1 Biological Activity Values For Stable Subgenonic HCV RepliconCell Lines EC₅₀ 1A EC₅₀ 1B EC₅₀ 2A EC₅₀ 3A EC₅₀ 4A Ki 1B Ki 3A RLUC*RLUC* RLUC* RLUC* RLUC* Example (nM) (nM) (nM) (nM) (nM) (nM) (nM) 10.03 0.07 4.4 3.9 4.1 46 3.1 2 0.01 0.04 4.0 3.1 3.9 77 2.7 3 0.18 0.5611.7 9.8 28 546 10 4 0.17 0.56 10.7 9.6 16 271 7.9 5 0.04 0.17 8.7 7.411 405 6.9 6 0.20 0.62 35 36 34 1361 34 7 0.05 0.06 4.9 3.8 4.2 67 3.2 80.07 0.42 16 8.6 20 465 13 9 0.15 0.59 17 7.9 23 1268 11 10 0.16 0.52 3022 49 978 26 11 0.23 0.88 28 17 34 1162 19 12 0.27 1.2 34 18 25 2013 2113 0.04 0.18 13 9.5 26 685 11 14 0.07 0.24 9.7 6.8 7.0 308 7.3 15 0.050.30 11 6.8 9.8 550 7.8 16 0.09 0.21 12 7.4 6.2 201 8.1 17 0.04 0.06 3.93.3 3.7 15 2.9 18 0.03 0.10 3.9 2.6 5.0 70 2.8 19 0.02 0.13 4.0 2.6 4.689 3.1 20 0.12 0.53 8.1 5.2 19 392 5.9 21 0.10 0.45 6.8 4.7 12 263 6.222 0.07 1.3 15 7.5 27 727 11 23 0.08 1.1 13 7.5 23 587 9.9 24 0.05 0.9212 7.5 20 663 9.2 25 0.05 0.39 8.8 6.3 13 409 7.1 26 0.05 0.17 6.3 4.312 297 6.0 27 0.03 0.08 6.6 5.2 6.7 266 6.1 28 0.03 0.08 6.7 4.6 6.2 2664.1 29 0.06 0.12 10 8.9 11 137 7.2 30 0.14 0.63 55 35 47 2437 31 31 0.134.9 40 18 63 2071 20 32 0.18 0.87 59 30 35 2311 30 33 0.03 0.06 7.6 2.84.9 16 2.3 34 0.10 0.28 12 13 18 322 9.7 35 0.07 0.23 9.1 11 7.4 162 7.636 0.10 1.7 23 14 53 585 9.1 37 0.10 0.19 24 22 16 575 15 38 0.03 0.707.8 4.2 5.4 151 5.5 39 0.08 0.20 34 39 41 321 26 40 0.08 0.18 25 22 48360 18 41 0.18 0.79 135 142 106 2606 135 42 0.10 0.75 20 16 17 343 14 430.06 0.16 4.9 3.8 5.2 92 3.6 44 0.03 0.08 3.1 2.1 2.9 53 2.2 45 0.040.48 21 8.3 24 549 13 46 0.03 0.05 3.1 2.7 3.8 17 2.5 47 0.07 0.19 3.83.6 12 58 4.2 48 0.07 0.09 2.0 1.8 9.7 73 2.2 49 0.04 0.07 3.7 4.1 5.220 3.5 50 63 100 4444 4444 379 19708 4444 51 0.31 0.84 40 39 103 1221 3052 0.25 1.3 195 245 380 2307 161 53 0.03 0.09 51 7.7 13 18 2.8 54 0.110.50 33 18 76 260 13 55 0.09 0.20 13 3.8 12 140 3.5 56 0.38 1.0 41 37 571026 57 57 0.07 0.28 12 11 21 166 4.9 58 0.07 0.17 12 9.7 12 134 12 590.04 0.06 5.4 11 13 20 5.6 60 0.04 0.08 11 4.8 7.7 45 5.4 61 0.06 0.0913 10 8.7 28 11 62 0.04 0.03 3.4 3.0 5.0 8.5 2.4 63 0.03 0.01 4.2 2.93.2 11 3.2 64 0.07 1.2 100 38 48 671 34 65 0.08 0.07 12 8.4 7.7 30 8.166 0.04 0.06 37 20 105 1786 25 67 0.04 0.32 11 12 24 383 12 68 0.05 0.6313 7.7 18 364 9.4 69 0.07 0.17 5.2 4.9 11 64 5.8 70 0.05 0.05 8.4 8.5 1541 6.4 71 0.03 0.14 6.5 5.3 23 160 5.3 72 0.05 4.1 365 300 740 1819 38373 0.11 0.82 7.9 7.5 22 178 7.2 74 0.03 0.12 8.0 5.0 18 374 8.3 75 0.030.12 9.9 6.4 18 240 10 76 0.03 0.06 2.4 2.2 2.4 9.0 1.9 77 nt nt 23 1229 741 16 78 0.21 0.82 267 394 195 1115 225 79 0.06 0.06 7.0 5.8 4.1 715.6 80 0.49 13 1127 344 748 44444 1182 81 0.04 0.05 4.0 3.6 3.6 12 4.382 0.03 0.04 8.5 9.3 4.7 25 10 83 0.09 0.48 62 58 19 1219 42 84 0.040.08 5.9 5.7 7.2 27 6.4 85 0.05 0.03 16 17 7.7 304 9.2 86 0.04 0.07 5.65.5 5.9 42 5.7 87 0.02 0.05 4.8 3.9 3.3 14 3.8 88 0.02 0.29 9.3 4.6 2.7105 4.1 89 0.03 0.05 6.0 6.1 4.3 19 4.6 90 0.06 0.13 12 9.6 8.8 114 10.491 nt nt 2.4 1.9 4.0 149 2.4 92 nt nt 3.3 3.2 4.6 58 3.2 93 nt nt 12 1415 116 11 94 nt nt 3.8 5.2 3.3 32 3.0 96 nt nt 12 11 5.4 77 8.9 97 nt nt6.3 4.6 5.8 67 5.3 nt—not tested *RULC: Renilla Luciferase

TABLE 2 Biological Activity Values For Transient-Transfected HCVReplicon Cell Lines EC₅₀ 3A EC₅₀1A EC₅₀ 1A EC₅₀1B EC₅₀1B WT* WT*R155K^(†) WT* D168A^(‡) (nM) (nM) (nM) (nM) (nM)  1 17 3.2 4.9 2.2 17  2nt 2.4 7.0 1.0 33  3 nt 6.6 32 3.5 128  4 68 7.1 20 6.5 66  5 nt 3.7 173.2 91  6 nt 26 58 11 216  7 14 3.8 6.7 2.3 20  8 nt 8.8 28 4.8 89  9 nt12 208 2.5 360 10 nt 37 131 10 493 11 nt 20 159 9.4 605 12 nt 14 283 5.7640 13 nt 8.6 59 3.1 209 14 nt 7.4 21 4.0 99 15 nt 6.5 20 3.0 182 16 nt9.4 22 5.8 61 17 6.1 2.9 2.8 1.7 4.3 18 nt 2.3 5.0 1.2 24 19 nt 2.1 3.41.1 28 20 Nt 3.4 17 2.7 90 21 nt 4.1 15 3.8 70 22 nt 8.6 48 2.6 242 23nt 9.5 36 3.6 173 24 nt 9.3 49 3.2 284 25 nt 4.4 17 3.6 116 26 nt 3.6 121.9 109 27 nt 6.0 20 4.3 70 28 nt 3.0 9 3.4 54 29 nt 4.8 11 3.1 48 30 nt41 296 31 503 31 nt 27 154 6.6 805 32 nt 44 547 14 653 33 5.3 2.6 2.51.6 4.2 34 46 15 18 9 64 35 35 12 17 10 38 36 128 16 271 9.4 333 37 6929 51 22 159 38 nt 4.5 8.4 2.8 25 39 89 23 63 16 105 40 156 17 74 8.6129 41 539 164 505 154 715 42 nt 17 35 10 109 43 nt 3.8 8.7 2.4 41 447.0 2.4 4.0 1.4 15 45 nt 13 35 5.3 88 46 6.788 2.4 3.2 1.2 4.5 47 17 5.46.1 2.0 12 48 13 1.7 4.0 1.1 6.5 49 6.3 3.5 3.8 2.8 4.2 50 26825 44443830 4444 4444 51 265 28 92 24 318 52 538 150 516 161 887 53 15 5.3 5.62.0 11 54 147 19 27 10 123 55 71 8.0 32 2.3 53 56 226 63 168 59 252 5754 12 17 7.5 48 58 38 12 18 14 23 59 15 10 6.8 6.8 6.4 60 9.8 5.8 8.62.3 15 61 13 12 10 9.3 6.7 62 4.0 3.5 2.7 1.5 2.0 63 6.9 4.1 4.0 2.1 3.464 256 37 50 17 104 65 17 9.4 8.1 6.4 11 66 735 35 240 14 396 67 107 1442 10 86 68 139 14 37 4.4 78 69 42 8.2 15 3.9 28 70 17 7.7 5.4 6.1 7.371 49 9.1 30 3.8 66 72 642 600 227 165 687 73 45 8.8 25 6.2 75 74 1388.8 44 2.1 56 75 56 14 45 3.5 51 76 3.4 2.0 2.1 1.0 2.8 77 472 21 34 5.080 78 194 189 225 156 248 79 9.2 6.1 7.1 3.0 11 80 nt 403 2862 53 443 814.3 3.7 2.5 2.4 2.7 82 16 7.8 6.2 4.1 5.7 83 300 62 133 27 202 84 11 5.44.0 2.5 5.2 85 101 12 22 7.0 57 86 16 4.0 3.7 3.4 10 87 7.7 2.9 2.8 1.34.0 88 35 5.0 14 5.5 24 89 5.5 6.0 3.7 3.2 5.1 90 43 nt nt nt nt 91 252.3 3.5 1.3 9.2 92 8.0 3.0 3.0 1.7 5.3 93 26 13 13 14 39 94 10 3.2 3.11.9 9.2 96 12 5.2 3.8 4.1 3.6 97 5.8 3.6 3.7 2.5 8.8 nt: not tested *WT= wild type ^(†)NS3/4a protease inhibitor resistant variants R155K ingenotype 1a ^(‡)NS3/4a protease inhibitor resistant variants D168A ingenotype 1b

The data in Tables 1 and 2 represent an average over time of each assaysfor each compound. For certain compounds, multiple assays have beenconducted over the life of the project. Thus, the data reported inTables 1 and 2 include the data reported in the priority document, aswell as data generated in the intervening period.

Pharmaceutical Compositions

The following illustrate representative pharmaceutical dosage forms,containing a compound of Formulas I, II, III, or IV (such as any one ofIVa-IVh) (‘Compound X’), for therapeutic or prophylactic use in humans.

(i) Tablet 1 mg/tablet Compound X = 100.0 Lactose 77.5 Povidone 15.0Croscarmellose sodium 12.0 Microcrystalline cellulose 92.5 Magnesiumstearate 3.0 300.0

(ii) Tablet 2 mg/tablet Compound X = 20.0 Microcrystalline cellulose410.0 Starch 50.0 Sodium starch glycolate 15.0 Magnesium stearate 5.0500.0

(iii) Capsule mg/capsule Compound X = 10.0 Colloidal silicon dioxide 1.5Lactose 465.5 Pregelatinized starch 120.0 Magnesium stearate 3.0 600.0

(iv) Injection (1 mq/ml) mq/ml Compound X = (free acid form) 1.0 Dibasicsodium phosphate 12.0 Monobasic sodium phosphate 0.7 Sodium chloride 4.51.0 N Sodium hydroxide solution q.s. (pH adjustment to 7.0-7.5) Waterfor injection q.s. ad 1 mL

The above formulations may be obtained by conventional procedures wellknown in the pharmaceutical art.

All references, including publications, patents, and patent documentsare incorporated by reference herein, as though individuallyincorporated by reference. The invention has been described withreference to various specific and preferred embodiments and techniques.However, it should be understood that many variations and modificationsmay be made while remaining within the spirit and scope of theinvention.

The use of the terms “a” and “an” and “the” and similar references inthe context of this disclosure (especially in the context of thefollowing claims) are to be construed to cover both the singular and theplural, unless otherwise indicated herein or clearly contradicted bycontext. All methods described herein can be performed in any suitableorder unless otherwise indicated herein or otherwise clearlycontradicted by context. The use of any and all examples, or exemplarylanguage (e.g., such as, preferred, preferably) provided herein, isintended merely to further illustrate the content of the disclosure anddoes not pose a limitation on the scope of the claims. No language inthe specification should be construed as indicating any non-claimedelement as essential to the practice of the present disclosure.

Alternative embodiments of the claimed disclosure are described herein,including the best mode known to the inventors for practicing theclaimed invention. Of these, variations of the disclosed embodimentswill become apparent to those of ordinary skill in the art upon readingthe foregoing disclosure. The inventors expect skilled artisans toemploy such variations as appropriate (e.g., altering or combiningfeatures or embodiments), and the inventors intend for the invention tobe practiced otherwise than as specifically described herein.

Accordingly, this invention includes all modifications and equivalentsof the subject matter recited in the claims appended hereto as permittedby applicable law. Moreover, any combination of the above describedelements in all possible variations thereof is encompassed by theinvention unless otherwise indicated herein or otherwise clearlycontradicted by context.

The use of individual numerical values is stated as approximations asthough the values were preceded by the word “about” or “approximately.”Similarly, the numerical values in the various ranges specified in thisapplication, unless expressly indicated otherwise, are stated asapproximations as though the minimum and maximum values within thestated ranges were both preceded by the word “about” or “approximately.”In this manner, variations above and below the stated ranges can be usedto achieve substantially the same results as values within the ranges.As used herein, the terms “about” and “approximately” when referring toa numerical value shall have their plain and ordinary meanings to aperson of ordinary skill in the art to which the disclosed subjectmatter is most closely related or the art relevant to the range orelement at issue. The amount of broadening from the strict numericalboundary depends upon many factors. For example, some of the factorswhich may be considered include the criticality of the element and/orthe effect a given amount of variation will have on the performance ofthe claimed subject matter, as well as other considerations known tothose of skill in the art. As used herein, the use of differing amountsof significant digits for different numerical values is not meant tolimit how the use of the words “about” or “approximately” will serve tobroaden a particular numerical value or range. Thus, as a generalmatter, “about” or “approximately” broaden the numerical value. Also,the disclosure of ranges is intended as a continuous range includingevery value between the minimum and maximum values plus the broadeningof the range afforded by the use of the term “about” or “approximately.”Thus, recitation of ranges of values herein are merely intended to serveas a shorthand method of referring individually to each separate valuefalling within the range, unless otherwise indicated herein, and eachseparate value is incorporated into the specification as if it wereindividually recited herein.

It is to be understood that any ranges, ratios and ranges of ratios thatcan be formed by, or derived from, any of the data disclosed hereinrepresent further embodiments of the present disclosure and are includedas part of the disclosure as though they were explicitly set forth. Thisincludes ranges that can be formed that do or do not include a finiteupper and/or lower boundary. Accordingly, a person of ordinary skill inthe art most closely related to a particular range, ratio or range ofratios will appreciate that such values are unambiguously derivable fromthe data presented herein.

What is claimed is:
 1. A compound of Formula (IV):

or a stereoisomer, or a mixture of stereoisomers, or a pharmaceuticallyacceptable salt thereof, wherein: J is C₁-C₄ alkyl or C₃-C₆ carbocyclyl,wherein the C₁-C₄ alkyl or C₃-C₆ carbocyclyl is optionally substitutedwith 1-4 halogen, —OH, aryl or cyano; {circle around (T)} is C₃-C₅carbocyclylene that is attached to L and to the remainder of thecompound of Formula IV through two adjacent carbons, wherein said C₃-C₅carbocyclylene is optionally substituted with C₁-C₄ alkyl, C₁-C₃haloalkyl, halogen, —OH, or cyano, or {circle around (T)} is C₅-C₈bicyclic carbocyclylene that is attached to L and to the remainder ofthe compound of Formula IV through two adjacent carbons, or C₃—C₆carbocyclylene that is attached to L and to the remainder of thecompound of Formula IV through two adjacent carbons, wherein said C₃—O₆carbocyclene is optionally substituted with C₁-C₄ alkyl or C₁-C₃haloalkyl; L is C₃-C₆ alkylene, C₃-C₆ alkenylene or—(CH₂)₃-cyclopropylene-, optionally substituted with 1-4 halogen, —OH,or cyano; Q is C₂-C₄ alkyl or C₃-C₆ carbocyclyl optionally substitutedwith C₁-C₃ alkyl, halogen, —OH, or cyano; E is C₁-C₃ alkyl or C₂-C₃alkenyl, optionally substituted with 1-3 halogen; W is H, —OH,—O(C₁-C₃)alkyl, —O(C₁-C₃)haloalkyl, halogen or cyano; and Z^(2a) is H orC₁-C₃ alkyl.
 2. The compound of claim 1, or a stereoisomer, or a mixtureof stereoisomers, or a pharmaceutically acceptable salt thereof, whereinJ is C₁-C₃ alkyl.
 3. The compound of claim 1, or a stereoisomer, or amixture of stereoisomers, or a pharmaceutically acceptable salt thereof,wherein J is methyl or ethyl.
 4. The compound of any one of claims 1 to3, or a stereoisomer, or a mixture of stereoisomers, or apharmaceutically acceptable salt thereof, wherein {circle around (T)} isC₃-C₆ carbocyclylene that is attached to L and to the remainder of thecompound of Formula IV through two adjacent carbons, wherein said C₃-C₆carbocyclene is optionally substituted with C₁-C₄ alkyl or C₁-C₃haloalkyl.
 5. The compound of any one of claims 1 to 3, or astereoisomer, or a mixture of stereoisomers, or a pharmaceuticallyacceptable salt thereof, wherein {circle around (T)} is C₃-C₆carbocyclylene that is attached to L and to the remainder of thecompound of Formula IV through two adjacent carbons, wherein the C₃-C₆carbocyclene is optionally substituted with methyl, ethyl ortrifluoromethyl.
 6. The compound of any one of claims 1 to 3, or astereoisomer, or a mixture of stereoisomers, or a pharmaceuticallyacceptable salt thereof, wherein {circle around (T)} is cyclopropylene.7. The compound of any one of claims 1 to 3, or a stereoisomer, or amixture of stereoisomers, or a pharmaceutically acceptable salt thereof,wherein {circle around (T)} is C₆-C₈ bridged bicyclic carbocyclylene orC₆-C₈ fused bicyclic carbocyclylene that is attached to L and to theremainder of the compound of Formula IV through two adjacent carbons. 8.The compound of any one of claims 1 to 7, or a stereoisomer, or amixture of stereoisomers, or a pharmaceutically acceptable salt thereof,wherein L is C₃-C₆ alkylene, substituted with 1-4 halogens.
 9. Thecompound of any one of claims 1 to 7, or a stereoisomer, or a mixture ofstereoisomers, or a pharmaceutically acceptable salt thereof, wherein Lis C₅ alkylene, substituted with two halogens.
 10. The compound of anyone of claims 1 to 7, or a stereoisomer, or a mixture of stereoisomers,or a pharmaceutically acceptable salt thereof, wherein L is C₃-C₆alkylene.
 11. The compound of any one of claims 1 to 7, or astereoisomer, or a mixture of stereoisomers, or a pharmaceuticallyacceptable salt thereof, wherein L is C₅ alkylene.
 12. The compound ofclaim 8 or claim 9, or a stereoisomer, or a mixture of stereoisomers, ora pharmaceutically acceptable salt thereof, wherein the halogens areeach fluoro.
 13. The compound of any one of claims 1 to 12, or astereoisomer, or a mixture of stereoisomers, or a pharmaceuticallyacceptable salt thereof, wherein Q is t-butyl or C₅-C₆ carbocyclyl. 14.The compound of any one of claims 1 to 12, or a stereoisomer, or amixture of stereoisomers, or a pharmaceutically acceptable salt thereof,wherein Q is t-butyl.
 15. The compound of any one of claims 1 to 14, ora stereoisomer, or a mixture of stereoisomers, or a pharmaceuticallyacceptable salt thereof, wherein E is C₁-C₃ alkyl optionally substitutedwith 1-3 halogen atoms.
 16. The compound of any one of claims 1 to 14,or a stereoisomer, or a mixture of stereoisomers, or a pharmaceuticallyacceptable salt thereof, wherein E is difluoromethyl.
 17. The compoundof any one of claims 1 to 16, or a stereoisomer, or a mixture ofstereoisomers, or a pharmaceutically acceptable salt thereof, wherein Wis hydrogen, —O(C₁-C₃)alkyl, halogen or cyano.
 18. The compound of anyone of claims 1 to 16, or a stereoisomer, or a mixture of stereoisomers,or a pharmaceutically acceptable salt thereof, wherein W is methoxy. 19.The compound of any one of claims 1 to 18, or a stereoisomer, or amixture of stereoisomers, or a pharmaceutically acceptable salt thereof,wherein Z^(2a) is hydrogen or methyl.
 20. The compound of any one ofclaims 1 to 18, or a stereoisomer, or a mixture of stereoisomers, or apharmaceutically acceptable salt thereof, wherein Z^(2a) is methyl.